A novel lncRNA-mediated epigenetic regulatory mechanism in periodontitis.

Periodontitis is a highly prevalent chronic inflammatory disease with an exaggerated host immune response, resulting in periodontal tissue destruction and potential tooth loss. The long non-coding RNA, LncR-ANRIL, located on human chromosome 9p21, is recognized as a genetic risk factor for various conditions, including atherosclerosis, periodontitis, diabetes, and cancer. LncR-APDC is an ortholog of ANRIL located on mouse genome chr4. This study aims to comprehend the regulatory role of lncR-APDC in periodontitis progression. Our experimental findings, obtained from lncR-APDC gene knockout (KO) mice with induced experimental periodontitis (EP), revealed exacerbated bone loss and disrupted pro-inflammatory cytokine regulation. Downregulation of osteogenic differentiation occurred in bone marrow stem cells harvested from lncR-APDC-KO mice. Furthermore, single-cell RNA sequencing of periodontitis gingival tissue revealed alterations in the proportion and function of immune cells, including T and B cells, macrophages, and neutrophils, due to lncR-APDC silencing. Our findings also unveiled a previously unidentified epithelial cell subset that is distinctively presenting in the lncR-APDC-KO group. This epithelial subset, characterized by the positive expression of Krt8 and Krt18, engages in interactions with immune cells through a variety of ligand-receptor pairs. The expression of Tff2, now recognized for its role in chronic inflammatory conditions, exhibited a notable increase across various tissue and cell types in lncR-APDC deficient mice. Additionally, our investigation revealed the potential for a direct binding interaction between lncR-APDC and Tff2. Intra-gingival administration of AAV9-lncR-APDC was shown to have therapeutic effects in the EP model. In conclusion, our results suggest that lncR-APDC plays a critical role in the progression of periodontal disease and holds therapeutic potential for periodontitis. Furthermore, the presence of the distinctive epithelial subpopulation and significantly elevated Tff2 levels in the lncR-APDC-silenced EP model offer new perspectives on the epigenetic regulation of periodontitis pathogenesis.

Noise induced complexity: from subthreshold oscillations to spiking in coupled excitable systems.

We study the stochastic dynamics of an ensemble of N globally coupled excitable elements. Each element is modeled by a FitzHugh-Nagumo oscillator and is disturbed by independent Gaussian noise. In simulations of the Langevin dynamics we characterize the collective behavior of the ensemble in terms of its mean field and show that with the increase of noise the mean field displays a transition from a steady equilibrium to global oscillations and then, for sufficiently large noise, back to another equilibrium. In the course of this transition diverse regimes of collective dynamics ranging from periodic subthreshold oscillations to large-amplitude oscillations and chaos are observed. In order to understand the details and mechanisms of these noise-induced dynamics we consider the thermodynamic limit N-->infinity of the ensemble, and derive the cumulant expansion describing temporal evolution of the mean field fluctuations. In Gaussian approximation this allows us to perform the bifurcation analysis; its results are in good qualitative agreement with dynamical scenarios observed in the stochastic simulations of large ensembles.

Noise-controlled oscillations and their bifurcations in coupled phase oscillators.

We derive in Gaussian approximation dynamical equations for the first two cumulants of the mean field fluctuations in a system of globally coupled stochastic phase oscillators. In these equations the intensity of noise serves as an explicit control parameter. Its variation generates transitions between three dynamical regimes: (i) stationary, (ii) rotatory and (iii) locally oscillatory (breathing). The latter regime has previously not been reported in studies of globally coupled noisy phase oscillators. Our detailed bifurcation analysis is supported by numerical simulations of an ensemble of coupled stochastic phase oscillators. Similar regimes are also found in simulations of globally coupled stochastic FitzHugh-Nagumo elements.

[Surgical treatment of breast neoplasms in early stages]. / Khirurhichne likuvannia raku molochnoï zalozy u rannikh stadiiakh.

Analysis of literary data and own investigation results for the modern surgical methods of treatment of mammary gland cancer in early stages was performed. Indexes of patients survival after surgical removal of mammary gland (MG) and quadranthectomy did not differ. Preservation of MG constitutes great social and psycho-emotional significance for women-patients.

Noise-induced phase synchronization enhanced by dichotomic noise.

We study the nonlinear response of a stochastic bistable system driven by both a weak periodic signal and a dichotomic noise in terms of stochastic phase synchronization. We show that the effect of noise-induced phase synchronization can be significantly enhanced by the addition of a dichotomic noise.

Entropy and local uncertainty of data from sensory neurons.

We present an empirical comparison between neural interspike interval sequences obtained from two different kinds of sensory receptors. Both differ in their internal structure as well as in the strength of correlations and the degree of predictability found in the respective spike trains. As a further tool in this context, we suggest the local uncertainty, assigning a well-defined predictability to individual spikes. The local uncertainty is demonstrated to reveal significant patterns within the interspike interval sequences, even when its overall structure is (almost) random. Our approach is based on the concept of symbolic dynamics and information theory.

Synchronization of hyperexcitable systems with phase-repulsive coupling.

We study two-dimensional arrays of FitzHugh-Nagumo elements with nearest-neighbor coupling from the viewpoint of synchronization. The elements are diffusively coupled. By varying the diffusion coefficient from positive to negative values, interesting synchronization patterns are observed. The results of the simulations resemble the intracellular oscillation patterns observed in cultured human epileptic astrocytes. Three measures are proposed to determine the degree of synchronization (or coupling) in both the simulated and the experimental system.

A Gip1p-Glc7p phosphatase complex regulates septin organization and spore wall formation.

Sporulation of Saccharomyces cerevisiae is a developmental process in which a single cell is converted into four haploid spores. GIP1, encoding a developmentally regulated protein phosphatase 1 interacting protein, is required for spore formation. Here we show that GIP1 and the protein phosphatase 1 encoded by GLC7 play essential roles in spore development. The gip1Delta mutant undergoes meiosis and prospore membrane formation normally, but is specifically defective in spore wall synthesis. We demonstrate that in wild-type cells, distinct layers of the spore wall are deposited in a specific temporal order, and that gip1Delta cells display a discrete arrest at the onset of spore wall deposition. Localization studies revealed that Gip1p and Glc7p colocalize with the septins in structures underlying the growing prospore membranes. Interestingly, in the gip1Delta mutant, not only is Glc7p localization altered, but septins are also delocalized. Similar phenotypes were observed in a glc7-136 mutant, which expresses a Glc7p defective in interacting with Gip1p. These results indicate that a Gip1p-Glc7p phosphatase complex is required for proper septin organization and initiation of spore wall formation during sporulation.

Noise-induced impulse pattern modifications at different dynamical period-one situations in a computer model of temperature encoding.

We used a minimal Hodgkin-Huxley type model of cold receptor discharges to examine how noise interferes with the non-linear dynamics of the ionic mechanisms of neuronal stimulus encoding. The model is based on the assumption that spike-generation depends on subthreshold oscillations. With physiologically plausible temperature scaling, it passes through different impulse patterns which, with addition of noise, are in excellent agreement with real experimental data. The interval distributions of purely deterministic simulations, however, exhibit considerable differences compared to the noisy simulations especially at the bifurcations of deterministically period-one discharges. We, therefore, analyzed the effects of noise in different situations of deterministically regular period-one discharges: (1) at high-temperatures near the transition to subthreshold oscillations and to burst discharges, and (2) at low-temperatures close to and more far away from the bifurcations to chaotic dynamics. The data suggest that addition of noise can considerably extend the dynamical behavior of the system with coexistence of different dynamical situations at deterministically fixed parameter constellations. Apart from well-described coexistence of spike-generating and subthreshold oscillations also mixtures of tonic and bursting patterns can be seen and even transitions to unstable period-one orbits seem to appear. The data indicate that cooperative effects between low- and high-dimensional dynamics have to be considered as qualitatively important factors in neuronal encoding.

SPO21 is required for meiosis-specific modification of the spindle pole body in yeast.

During meiosis II in the yeast Saccharomyces cerevisiae, the cytoplasmic face of the spindle pole body changes from a site of microtubule initiation to a site of de novo membrane formation. These membranes are required to package the haploid meiotic products into spores. This functional change in the spindle pole body involves the expansion and modification of its cytoplasmic face, termed the outer plaque. We report here that SPO21 is required for this modification. The Spo21 protein localizes to the spindle pole in meiotic cells. In the absence of SPO21 the structure of the outer plaque is abnormal, and prospore membranes do not form. Further, decreased dosage of SPO21 leaves only two of the four spindle pole bodies competent to generate membranes. Mutation of CNM67, encoding a known component of the mitotic outer plaque, also results in a meiotic outer plaque defect but does not block membrane formation, suggesting that Spo21p may play a direct role in initiating membrane formation.

Stochastic biperiodic oscillations in the electroreceptors of paddlefish.

We report that the electroreceptors in paddlefish possess the novel property of being biperiodic, that is, being composed of two intrinsic self-sustained noisy oscillators, one residing in the hair cells, and another in the terminals of primary afferent neurons. The two oscillators are coupled unidirectionally. Thus the receptor system as a whole undergoes stochastic biperiodic oscillations. We characterize the spontaneous activity of this system of coupled biological oscillators, and also discuss the impact of the biperiodic organization on the transduction of external sensory stimuli. In particular, we show that the existence of hair cell oscillations leads to additional variability of afferent spike trains.

Behavioral stochastic resonance: how a noisy army betrays its outpost.

Juvenile paddlefish prey upon single zooplankton by detecting a weak electric signature resulting from its feeding and swimming motions. Moreover, it has recently been shown that paddlefish make use of stochastic resonance near the threshold for prey detection: a process termed behavioral stochastic resonance. But this process depends upon an external source of electric noise. A swarm of plankton, for example, Daphnia, can provide this noise. Assuming that juvenile paddlefish attack single Daphnia as outliers in the vicinity of the swarm, making use of noise from the swarm, we calculate the spatial distribution of the average phase locking period for the subthreshold signals acting at the paddlefish rostrum. Numeric evaluation of analytic formulas supports the notion of a noise-induced widening of the capture area quantitatively.

Stochastic resonance enhanced by dichotomic noise in a bistable system

We study linear responses of a stochastic bistable system driven by dichotomic noise to a weak periodic signal. We show that the effect of stochastic resonance can be greatly enhanced in comparison with the conventional case when dichotomic forcing is absent, that is, both the signal-to-noise ratio and the spectral power amplification reach much greater values than in the standard stochastic resonance setup.

Cutaneous manifestations of neonatal lupus without heart block: characteristics of mothers and children enrolled in a national registry.

OBJECTIVE: To extend the information base on cutaneous manifestations of neonatal lupus erythematosus (NLE) with regard to maternal disease, sex of child, onset, localization, influence of UV light, prognosis, and recurrence rates in subsequent pregnancies. METHODS: Review of records from the Research Registry for Neonatal Lupus. RESULTS: The cohort includes 47 mothers (83% white) whose sera contain anti-SSA/Ro, anti-SSB/La, and/or anti-U1-ribonucleoprotein antibodies and their 57 infants (20 boys and 37 girls) diagnosed with cutaneous NLE (absent heart disease) between 1981 and 1997. At detection of the child's rash, 13 mothers were asymptomatic, 11 had an undifferentiated autoimmune syndrome (UAS), 9 had systemic lupus erythematosus (SLE), 7 Sjögren's syndrome (SS), 6 SLE/SS, and 1 rheumatoid arthritis/SS; 20 reported photosensitivity. Within 5 years, 7 asymptomatic mothers experienced disease progression: 1 developed photosensitivity, 2 SLE, 3 SS, 1 SLE/SS; in 2 mothers UAS progressed to SLE; and 2 mothers with SS developed SLE. The infant's rash often followed UV light exposure; mean age at detection was 6 weeks, and mean duration was 17 weeks. All had facial involvement (periorbital region most common) followed by the scalp, trunk, extremities, neck, and intertriginous areas. In 37, the rash resolved without sequelae, 43% of which were untreated. A quarter had residual sequelae that included telangiectasia and dyspigmentation. One child developed Hashimoto's thyroiditis, and 2 developed systemic-onset juvenile rheumatoid arthritis. Of 20 subsequent births, 7 children were healthy, 2 had congenital heart block (CHB) only, 4 CHB and skin rash, and 7 skin rash only. CONCLUSIONS: Future pregnancies should be monitored by serial echocardiograms, given the substantial risk for heart block. Affected children should be observed for later development of a rheumatic disease.

Detecting the onset of bifurcations and their precursors from noisy data

We study the problem of the detection of noise-induced precursors of periodic motion instabilities in stochastic dynamical systems. In particular, we concentrate on the period-doubling bifurcation. We have developed a statistical method to detect the onset of bifurcations and their precursors based on the previously established topological recurrence technique.

Stochastic resonance enhances the electrosensory information available to paddlefish for prey capture.

Recent behavior experiments have demonstrated that paddlefish can make use of stochastic resonance while feeding on Daphnia plankton. Here we calculate the information content of the noisy Daphnia signal at the paddlefish rostrum using an exact statistical treatment of threshold stochastic resonance as a minimal neural model. These calculations compare well with experimentally obtained data on paddlefish strikes at Daphnia prey.

BUR1 and BUR2 encode a divergent cyclin-dependent kinase-cyclin complex important for transcription in vivo.

BUR1 and BUR2 were previously identified by a genetic selection for mutations that increase transcription from basal promoters in vivo. BUR1 encoded a putative protein kinase with greatest similarity to members of the cyclin-dependent kinase (CDK) family, although that similarity was not sufficient to classify it as a CDK. It was also not known whether Bur1 activity was cyclin dependent and, if so, which cyclins stimulated Bur1. The molecular cloning and characterization of BUR2 presented here sheds light on these issues. Genetic analysis indicates that BUR2 function is intimately related to that of BUR1: bur1 and bur2 mutations cause nearly identical spectra of mutant phenotypes, and overexpression of BUR1 suppresses a bur2 null allele. Biochemical analysis has provided a molecular basis for these genetic observations. We find that BUR2 encodes a cyclin for the Bur1 protein kinase, based on the following evidence. First, the BUR2 amino acid sequence reveals similarity to the cyclins; second, Bur1 and Bur2 coimmunoprecipitate from crude extracts and interact in the two-hybrid system; and third, BUR2 is required for Bur1 kinase activity in vitro. Our combined genetic and biochemical results therefore indicate that Bur1 and Bur2 comprise a divergent CDK-cyclin complex that has an important functional role during transcription in vivo.

Identification of domains required for developmentally regulated SNARE function in Saccharomyces cerevisiae.

Saccharomyces cerevisiae cells contain two homologues of the mammalian t-SNARE protein SNAP-25, encoded by the SEC9 and SPO20 genes. Although both gene products participate in post-Golgi vesicle fusion events, they cannot substitute for one another; Sec9p is active primarily in vegetative cells while Spo20p functions only during sporulation. We have investigated the basis for the developmental stage-specific differences in the function of these two proteins. Localization of the other plasma membrane SNARE subunits, Ssop and Sncp, in sporulating cells suggests that these proteins act in conjunction with Spo20p in the formation of the prospore membrane. In vitro binding studies demonstrate that, like Sec9p, Spo20p binds specifically to the t-SNARE Sso1p and, once bound to Sso1p, can complex with the v-SNARE Snc2p. Therefore, Sec9p and Spo20p interact with the same binding partners, but developmental conditions appear to favor the assembly of complexes with Spo20p in sporulating cells. Analysis of chimeric Sec9p/Spo20p molecules indicates that regions in both the SNAP-25 domain and the unique N terminus of Spo20p are required for activity during sporulation. Additionally, the N terminus of Spo20p is inhibitory in vegetative cells. Deletion studies indicate that activation and inhibition are separable functions of the Spo20p N terminus. Our results reveal an additional layer of regulation of the SNARE complex, which is necessary only in sporulating cells.

Phosphorylation of the MEKK Ste11p by the PAK-like kinase Ste20p is required for MAP kinase signaling in vivo.

BACKGROUND: Many signals are transduced from the cell surface to the nucleus through mitogen-activated protein (MAP) kinase cascades. Activation of MAP kinase requires phosphorylation by MEK, which in turn is controlled by Raf, Mos or a group of structurally related kinases termed MEKKs. It is not understood how MEKKs are regulated by extracellular signals. In yeast, the MEKK Ste11p functions in multiple MAP kinase cascades activated in response to pheromones, high osmolarity and nutrient starvation. Genetic evidence suggests that the p21-activated protein kinase (PAK) Ste20p functions upstream of Ste11p, and Ste20p has been shown to phosphorylate Ste11p in vitro. RESULTS: Ste20p phosphorylated Ste11p on Ser302 and/or Ser306 and Thr307 in yeast, residues that are conserved in MEKKs of other organisms. Mutating these sites to non-phosphorylatable residues abolished Ste11p function, whereas changing them to aspartic acid to mimic the phosphorylated form constitutively activated Ste11p in vivo in a Ste20p-independent manner. The amino-terminal regulatory domain of Ste11p interacted with its catalytic domain, and overexpression of a small amino-terminal fragment of Ste11p was able to inhibit signaling in response to pheromones. Mutational analysis suggested that this interaction was regulated by phosphorylation and dependent on Thr596, which is located in the substrate cleft of the catalytic domain. CONCLUSIONS: Our results suggest that, in response to multiple extracellular signals, phosphorylation of Ste11p by Ste20p removes an amino-terminal inhibitory domain, leading to activation of the Ste11 protein kinase. This mechanism may serve as a paradigm for the activation of mammalian MEKKs.

Surrogates for finding unstable periodic orbits in noisy data sets.

Recently, searches for unstable periodic orbits in biological and medical applications have become of interest. The motivations for this research range, in order of ascending complexity, from efforts to understand the dynamics of simple sensory neurons, through speculations regarding neural coding, to the hopeful development of new diagnostic and/or control techniques for cardiac and epileptic pathologies. Biological and medical data are, however, noisy and nonstationary. Findings of unstable periodic orbits in such data thus require convincing assessments of their statistical significance. Such tests are accomplished by comparison with surrogate data files designed to test an appropriate null hypothesis. In this paper we test surrogates generated by three different algorithms against correlated noise as well as stable periodic orbits. One of the surrogates is new, and has been specifically designed to preserve the shape of the attractor. We discuss the suitability of these surrogates and argue that the simple shuffled one correctly tests the appropriate null hypothesis.