Characterizing mixed mode oscillations shaped by noise and bifurcation structure

Many neuronal systems and models display a certain class of mixed mode oscillations (MMOs) consisting of periods of small amplitude oscillations interspersed with spikes. Various models with different underlying mechanisms have been proposed to generate this type of behavior. Stochastic versions of these models can produce similarly looking time series, often with noise-driven mechanisms different from those of the deterministic models. We present a suite of measures which, when applied to the time series, serves to distinguish models and classify routes to producing MMOs, such as noise-induced oscillations or delay bifurcation. By focusing on the subthreshold oscillations, we analyze the interspike interval density, trends in the amplitude and a coherence measure. We develop these measures on a biophysical model for stellate cells and a phenomenological FitzHugh-Nagumo-type model and apply them on related models. The analysis highlights the influence of model parameters and reset and return mechanisms in the context of a novel approach using noise level to distinguish model types and MMO mechanisms. Ultimately, we indicate how the suite of measures can be applied to experimental time series to reveal the underlying dynamical structure, while exploiting either the intrinsic noise of the system or tunable extrinsic noise.Comment: 22 page

Expression of the mismatch repair gene hMLH1 is enhanced in non-small cell lung cancer with EGFR mutations

Mismatch repair (MMR) plays a pivotal role in keeping the genome stable. MMR dysfunction can lead to carcinogenesis by gene mutation accumulation. HMSH2 and hMLH1 are two key components of MMR. High or low expression of them often mark the status of MMR function. Mutations (EGFR, KRAS, etc) are common in non-small cell lung cancer (NSCLC). However, it is not clear what role MMR plays in NSCLC gene mutations. The expression of MMR proteins hMSH2 and hMLH1, and the proliferation markers PCNA and Ki67 were measured by immunohistochemistry in 181 NSCLCs. EGFR and KRAS mutations were identified by high resolution melting analysis. Stronger hMLH1 expression correlated to a higher frequency of EGFR mutations in exon 19 and 21 (p<0.0005). Overexpression of hMLH1 and the adenocarcinoma subtype were both independent factors that related to EGFR mutations in NSCLCs (p=0.013 and p<0.0005). The expression of hMLH1, hMSH2 and PCNA increased, while Ki67 expression significantly decreased (p=0.030) in NSCLCs with EGFR mutations. Overexpression of hMLH1 could be a new molecular marker to predict the response to EGFR-TKIs in NSCLCs. Furthermore, EGFR mutations might be an early event of NSCLC that occur before MMR dysfunction.This work was supported by the National Nature Science Funds in China (Fund No. 81071805; URL: http://isisn.nsfc.gov.cn/egrantweb/), and Dalian Merricon Gene Diagnosis Technology Co., Ltd. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Osteoblasts from osteoarthritis patients show enhanced susceptibility to Ross River virus infection associated with delayed type I interferon responses

BACKGROUND Arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) have caused widespread outbreaks of chronic polyarthritis. The inflammatory responses in alphavirus-induced arthritis and osteoarthritis (OA) share many similar features, which suggests the possibility of exacerbated alphavirus-induced bone pathology in individuals with pre-existing OA. Here, we investigated the susceptibility of osteoblasts (OBs) from OA patients to RRV infection and dissected the immune mechanisms elicited from infection. METHODS Primary hOBs obtained from trabecular bone of healthy donors and OA patients were infected with RRV. Infectivity and viral replication were determined using flow cytometry and plaque assay, respectively. Real-time PCR was performed to determine expression kinetics of type I interferon (IFN)-related immune mediators and osteotropic factors. RESULTS OA hOBs showed enhanced RRV infectivity and replication during infection, which was associated with delayed induction of IFN-β and RIG-I expression. Enhanced susceptibility of OA hOBs to RRV was associated with a more pronounced increase in RANKL/OPG ratio and expression of osteotropic factors (IL-6, IL-1β, TNF-α and CCL2) in comparison to RRV-infected healthy hOBs. CONCLUSIONS Delayed activation of type I IFN-signalling pathway may have contributed to enhanced susceptibility to RRV infection in hOBs from OA patients. RRV-induced increases in RANKL/OPG ratio and expression of osteotropic factors that favour bone resorption, which may be exacerbated during osteoarthritis. This study provides the novel insight that osteoarthritis may be a risk factor for exacerbated arthritogenic alphaviral infection.SM is the recipient of an Australian National Health and Medical Research Council (NHMRC) Senior Research Fellowship (APP1059167). This project was supported by funding from the Australian NHMRC grant to SM (grant APP1047252)

Ubiquitylation activates a peptidase that promotes cleavage and destabilization of its activating E3 ligases and diverse growth regulatory proteins to limit cell proliferation in Arabidopsis

The characteristic shapes and sizes of organs are established by cell proliferation patterns and final cell sizes, but the underlying molecular mechanisms coordinating these are poorly understood. Here we characterize a ubiquitin-activated peptidase called DA1 that limits the duration of cell proliferation during organ growth in Arabidopsis thaliana. The peptidase is activated by two RING E3 ligases, Big Brother (BB) and DA2, which are subsequently cleaved by the activated peptidase and destabilized. In the case of BB, cleavage leads to destabilization by the RING E3 ligase PROTEOLYSIS 1 (PRT1) of the N-end rule pathway. DA1 peptidase activity also cleaves the deubiquitylase UBP15, which promotes cell proliferation, and the transcription factors TEOSINTE BRANCED 1/ CYCLOIDEA/PCF 15 (TCP15) and TCP22, which promote cell proliferation and repress endoreduplication. We propose that DA1 peptidase activity regulates the duration of cell proliferation and the transition to endoreduplication and differentiation during organ formation in plants by coordinating the destabilization of regulatory proteins

Relaxation effect of abacavir on rat basilar arteries

Background The use of abacavir has been linked with increased cardiovascular risk in patients with human immunodeficiency virus infection; however, the mechanism involved remains unclear. We hypothesize that abacavir may impair endothelial function. In addition, based on the structural similarity between abacavir and adenosine, we propose that abacavir may affect vascular contractility through endogenous adenosine release or adenosine receptors in blood vessels. Methods The relaxation effect of abacavir on rat basilar arteries was studied using the myograph technique. Cyclic GMP and AMP levels were measured by immunoassay. The effects of abacavir on nucleoside transporters were studied using radiolabeled nucleoside uptake experiments. Ecto-5′ nucleotidase activity was determined by measuring the generation of inorganic phosphate using adenosine monophosphate as the substrate. Results Abacavir induced the relaxation of rat basilar arteries in a concentration-dependent manner. This relaxation was abolished when endothelium was removed. In addition, the relaxation was diminished by the nitric oxide synthase inhibitor, L-NAME, the guanylyl cyclase inhibitor, ODQ, and the protein kinase G inhibitor, KT5820. Abacavir also increased the cGMP level in rat basilar arteries. Abacavir-induced relaxation was also abolished by adenosine A2 receptor blockers. However, abacavir had no effect on ecto-5’ nucleotidase and nucleoside transporters. Short-term and long-term treatment of abacavir did not affect acetylcholine-induced relaxation in rat basilar arteries. Conclusion Abacavir induces acute endothelium-dependent relaxation of rat basilar arteries, probably through the activation of adenosine A2 receptors in endothelial cells, which subsequently leads to the release of nitric oxide, resulting in activation of the cyclic guanosine monophosphate/protein kinase G-dependent pathway in vascular smooth muscle cells. It is speculated that abacavir-induced cardiovascular risk may not be related to endothelial dysfunction as abacavir does not impair relaxation of blood vessels. The most likely explanation of increased cardiovascular risk may be increased platelet aggregation as suggested by other studies

Electrostatically gated membrane permeability in inorganic protocells

Although several strategies are now available to produce functional microcompartments analogous to primitive cell-like structures, little progress has been made in generating protocell constructs with self-controlled membrane permeability. Here we describe the preparation of water-dispersible colloidosomes based on silica nanoparticles and delineated by a continuous semipermeable inorganic membrane capable of self-activated, electrostatically gated permeability. We use crosslinking and covalent grafting of a pH-responsive copolymer to generate an ultrathin elastic membrane that exhibits selective release and uptake of small molecules. This behaviour, which depends on the charge of the copolymer coronal layer, serves to trigger enzymatic dephosphorylation reactions specifically within the protocell aqueous interior. This system represents a step towards the design and construction of alternative types of artificial chemical cells and protocell models based on spontaneous processes of inorganic self-organization

ALMA CN Zeeman Observations of AS 209: Limits on Magnetic Field Strength and Magnetically Driven Accretion Rate

While magnetic fields likely play an important role in driving the evolution of protoplanetary disks through angular momentum transport, observational evidence of magnetic fields has only been found in a small number of disks. Although dust continuum linear polarization has been detected in an increasing number of disks, its pattern is more consistent with that from dust scattering than from magnetically aligned grains in the vast majority of cases. Continuum linear polarization from dust grains aligned to a magnetic field can reveal information about the magnetic field´s direction, but not its strength. On the other hand, observations of circular polarization in molecular lines produced by Zeeman splitting offer a direct measure of the line-of-sight magnetic field strength in disks. We present upper limits on the net toroidal and vertical magnetic field strengths in the protoplanetary disk AS 209 derived from Zeeman splitting observations of the CN 2-1 line. The 3σ upper limit on the net line-of-sight magnetic field strength in AS 209 is 5.0 mG on the redshifted side of the disk and 4.2 mG on the blueshifted side of the disk. Given the disk´s inclination angle, we set a 3σ upper limit on the net toroidal magnetic field strength of 8.7 and 7.3 mG for the red and blue sides of the disk, respectively, and 6.2 and 5.2 mG on the net vertical magnetic field on the red and blue sides of the disk. If magnetic disk winds are a significant mechanism of angular momentum transport in the disk, magnetic fields of a strength close to the upper limits would be sufficient to drive accretion at the rate previously inferred for regions near the protostar.Fil: Harrison, Rachel. University of Illinois at Urbana; Estados UnidosFil: Looney, L. W.. University of Illinois at Urbana; Estados UnidosFil: Stephens, I. W.. Harvard-Smithsonian Center for Astrophysics; Estados UnidosFil: Li, Z.-Y.. University of Virginia; Estados UnidosFil: Teague, Richard. Department Of Astronomy; Estados UnidosFil: Crutcher, Richard. University of Illinois at Urbana; Estados UnidosFil: Yang, H.. Tsinghua University; ChinaFil: Cox, E. G.. Northwestern University; Estados UnidosFil: Fernandez Lopez, Manuel. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Argentino de Radioastronomía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Argentino de Radioastronomía; ArgentinaFil: Shinnaga, H.. Kagoshima University; Japó

Aligned Grains and Scattered Light Found in Gaps of Planet-Forming Disk

Polarized (sub)millimeter emission from dust grains in circumstellar disks was initially thought to be due to grains aligned with the magnetic field. However, higher resolution multi-wavelength observations along with improved models found that this polarization is dominated by self-scattering at shorter wavelengths (e.g., 870 $\mu$m) and by grains aligned with something other than magnetic fields at longer wavelengths (e.g., 3 mm). Nevertheless, the polarization signal is expected to depend on the underlying substructure, and observations hitherto have been unable to resolve polarization in multiple rings and gaps. HL Tau, a protoplanetary disk located 147.3 $\pm$ 0.5 pc away, is the brightest Class I or Class II disk at millimeter/submillimeter wavelengths. Here we show deep, high-resolution 870 $\mu$m polarization observations of HL Tau, resolving polarization in both the rings and gaps. We find that the gaps have polarization angles with a significant azimuthal component and a higher polarization fraction than the rings. Our models show that the disk polarization is due to both scattering and emission from aligned effectively prolate grains. The intrinsic polarization of aligned dust grains is likely over 10%, which is much higher than what was expected in low resolution observations (~1%). Asymmetries and dust features are revealed in the polarization observations that are not seen in non-polarimetric observations.Comment: Published in Natur

Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse

BACKGROUND: Neoplasia can be driven by mutations resulting in dysregulation of transcription. In the mesenchymal neoplasm, aggressive fibromatosis, subtractive hybridization identified sterile alpha motif domain 9 (SAMD9) as a substantially down regulated gene in neoplasia. SAMD9 was recently found to be mutated in normophosphatemic familial tumoral calcinosis. In this study, we studied the gene structure and function of SAMD9, and its paralogous gene, SAMD9L, and examined these in a variety of species. RESULTS: SAMD9 is located on human chromosome 7q21.2 with a paralogous gene sterile alpha motif domain 9 like (SAMD9L) in the head-to-tail orientation. Although both genes are present in a variety of species, the orthologue for SAMD9 is lost in the mouse lineage due to a unique genomic rearrangement. Both SAMD9 and SAMD9L are ubiquitously expressed in human tissues. SAMD9 is expressed at a lower level in a variety of neoplasms associated with β-catenin stabilization, such as aggressive fibromatosis, breast, and colon cancers. SAMD9 and SAMD9L contain an amino-terminal SAM domain, but the remainder of the predicted protein structure does not exhibit substantial homology to other known protein motifs. The putative protein product of SAMD9 localizes to the cytoplasm. In vitro data shows that SAMD9 negatively regulates cell proliferation. Over expression of SAMD9 in the colon cancer cell line, SW480, reduces the volume of tumors formed when transplanted into immune-deficient mice. CONCLUSION: SAMD9 and SAMD9L are a novel family of genes, which play a role regulating cell proliferation and suppressing the neoplastic phenotype. This is the first report as far as we know about a human gene that exists in rat, but is lost in mouse, due to a mouse specific rearrangement, resulting in the loss of the SAMD9 gene