The role of polyadenylation in the induction of inflammatory genes

Polyadenylation is a universal step in the production of all metazoan mRNAs except histone mRNA. Despite being universal, previous experiments have implicated it in the regulation of inflammation. An inflammatory system using RAW 264.7 murine macrophage cells was established with bacterial lipopolysaccharide (LPS) used as a stimulus. After improving the poly(A) tail test (PAT) method of measuring poly(A) tail lengths, it was applied to inflammatory mRNAs during the inflammatory response. Poly(A) tail length was shown to vary over the course of the inflammatory response, and for Tnf, this was even true of initial poly(A) tail size, which is widely believed to be uniform for the majority of mRNAs. The adenosine analogue cordycepin (3’-deoxyadenosine) was shown to have anti-inflammatory effects on mRNA, in line with existing literature, and is likely to be the anti-inflammatory component of Cordyceps militaris ethanol extract. Inhibition of either import of cordycepin into cells or phosphorylation of cordycepin was sufficient to abolish its anti-inflammatory effects. Adenosine treatment led to repression of Il1b mRNA, but did not repress other mRNAs tested that were cordycepin-sensitive. This suggests that cordycepin does not simply act by mimicking the effect of adenosine, and that the two compounds have distinct modes of action. Inhibiting deamination of cordycepin potentiated its effects. We also observed that pre-mRNA levels of inflammatory genes were decreased by cordycepin treatment, indicative of effects on transcription. Other groups have reported that cordycepin interferes with NF-B signalling. As NF-B is an important transcription factor for the induction of inflammatory genes, this would provide a basis for explaining our observation that cordycepin represses at the transcriptional level. However, we did not observe any changes in NF-B signalling, with degradation of IB completely unimpeded by cordycepin treatment. Notably, cordycepin did shorten the Tnf poly(A) tail, and the observed inhibition of polyadenylation is consistent with observations that cordycepin led to decreased efficiencies of mRNA 3’ cleavage and transcription termination for Tnf. Such effects on polyadenylation and 3’ processing of mRNA were hypothesised to particularly affect unstable mRNAs that depend on longer poly(A) tails for avoiding decay and/or mRNAs with a high rate of transcription. However, comparison of microarray data to data from RNA-seq of RNA from 4-thiouridine labelling experiments showed that cordycepin-sensitivity did not correlate with mRNA stability or transcription rate. Long noncoding RNAs (lncRNAs) were found to be enriched in cordycepin-treated cells. If some of those lncRNAs have regulatory roles in inflammation, cordycepin’s effects may be mediated through them. Lastly, cordycepin significantly altered pain behaviour in a rat model of osteoarthritis (OA), supporting its continued use as a lead compound for exploration of new OA therapeutics

The role of polyadenylation in the induction of inflammatory genes

Polyadenylation is a universal step in the production of all metazoan mRNAs except histone mRNA. Despite being universal, previous experiments have implicated it in the regulation of inflammation. An inflammatory system using RAW 264.7 murine macrophage cells was established with bacterial lipopolysaccharide (LPS) used as a stimulus. After improving the poly(A) tail test (PAT) method of measuring poly(A) tail lengths, it was applied to inflammatory mRNAs during the inflammatory response. Poly(A) tail length was shown to vary over the course of the inflammatory response, and for Tnf, this was even true of initial poly(A) tail size, which is widely believed to be uniform for the majority of mRNAs. The adenosine analogue cordycepin (3’-deoxyadenosine) was shown to have anti-inflammatory effects on mRNA, in line with existing literature, and is likely to be the anti-inflammatory component of Cordyceps militaris ethanol extract. Inhibition of either import of cordycepin into cells or phosphorylation of cordycepin was sufficient to abolish its anti-inflammatory effects. Adenosine treatment led to repression of Il1b mRNA, but did not repress other mRNAs tested that were cordycepin-sensitive. This suggests that cordycepin does not simply act by mimicking the effect of adenosine, and that the two compounds have distinct modes of action. Inhibiting deamination of cordycepin potentiated its effects. We also observed that pre-mRNA levels of inflammatory genes were decreased by cordycepin treatment, indicative of effects on transcription. Other groups have reported that cordycepin interferes with NF-B signalling. As NF-B is an important transcription factor for the induction of inflammatory genes, this would provide a basis for explaining our observation that cordycepin represses at the transcriptional level. However, we did not observe any changes in NF-B signalling, with degradation of IB completely unimpeded by cordycepin treatment. Notably, cordycepin did shorten the Tnf poly(A) tail, and the observed inhibition of polyadenylation is consistent with observations that cordycepin led to decreased efficiencies of mRNA 3’ cleavage and transcription termination for Tnf. Such effects on polyadenylation and 3’ processing of mRNA were hypothesised to particularly affect unstable mRNAs that depend on longer poly(A) tails for avoiding decay and/or mRNAs with a high rate of transcription. However, comparison of microarray data to data from RNA-seq of RNA from 4-thiouridine labelling experiments showed that cordycepin-sensitivity did not correlate with mRNA stability or transcription rate. Long noncoding RNAs (lncRNAs) were found to be enriched in cordycepin-treated cells. If some of those lncRNAs have regulatory roles in inflammation, cordycepin’s effects may be mediated through them. Lastly, cordycepin significantly altered pain behaviour in a rat model of osteoarthritis (OA), supporting its continued use as a lead compound for exploration of new OA therapeutics

Molecular Sequence of Events and Signaling Pathways in Cerebral Metastases

Brain metastases are the leading cause of morbidity and mortality among cancer patients, and are reported to occur in about 40% of cancer patients with metastatic disease in the United States of America. Primary tumor cells appear to detach from the parent tumor site, migrate, survive and pass through the blood brain barrier in order to establish cerebral metastases. This complex process involves distinct molecular and genetic mechanisms that mediate metastasis from these primary organs to the brain. Furthermore, an interaction between the invading cells and cerebral milieu is shown to promote this process as well. Here, we review the mechanisms by which primary cancer cells metastasize to the brain via a mechanism called epithelial-to-mesenchymal transition, as well as the involvement of certain microRNA and genetic aberrations implicated in cerebral metastases from the lung, breast, skin, kidney and colon. While the mechanisms governing the development of brain metastases remain a major hindrance in treatment, understanding and identification of the aforementioned molecular pathways may allow for improved management and discovery of novel therapeutic targets

Anticipatory anti-colonial writing in R.K. Narayan's Swami and Friends and Mulk Raj Anand's Untouchable

This article uses the term “anticipatory anti-colonial writing” to discuss the workings of time in R.K. Narayan’s Swami and Friends and Mulk Raj Anand’s Untouchable. Both these first novels were published in 1935 with the support of British literary personalities (Graham Greene and E.M. Forster respectively) and both feature young protagonists who, in contrasting ways, are engaged in Indian resistance to colonial rule. This study examines the difference between Narayan’s local, though ironical, resistance to the homogenizing temporal demands of empire and Anand’s awkwardly modernist, socially committed vision. I argue that a form of anticipation that explicitly looks forward to decolonization via new and transnational literary forms is a crucial feature of Untouchable that is not found in Swami and Friends, despite the latter’s anti-colonial elements. Untouchable was intended to be a “bridge between the Ganges and the Thames” and anticipates postcolonial negotiations of time that critique global inequalities and rely upon the multidirectional global connections forged by modernism

Two-Loop Neutrino Masses and the Solar Neutrino Problem

The addition of $m$ singlet right-handed neutrinos to the Standard Model leads to radiatively generated mass corrections for the $SU(2)_L$ doublet neutrinos. For those neutrinos which are massless at the tree level after this addition, this implies a small mass generated at the two-loop level via $W^{\pm}$ exchange. We calculate these mass corrections exactly by obtaining an analytic form for the general case of $n$ doublets and $m$ singlets. As a phenomenological application, we consider the $m=1$ case and examine the masses and mixings of the doublet neutrinos which arise as a result of the two-loop correction in the light of experimental data from two sources which may shed light on the question of neutrino masses. These are(a) the neutrino detectors reporting a solar neutrino deficit (and its resolution via Mikheyev-Smirnov-Wolfenstein matter oscillations), and (b) the COBE satellite data on the non-zero angular variations of the cosmic microwave background temperature (and its possible implications for hot dark matter). Within the framework of the extension considered here, which leaves the gauge group structure of the Standard Model intact, we show that it is possible for neutrinos to acquire small masses naturally, with values which are compatible with current theoretical bias and experimental data.Comment: 24 pages, Two figures, attached as postscript files at the end, Latex, CTP-TAMU-76/93, MRI-PHY-12/93, LTH-32

Signals of R-parity violating supersymmetry in neutrino scattering at muon storage rings

Neutrino oscillation signals at muon storage rings can be faked by supersymmetric (SUSY) interactions in an R-parity violating scenario. We investigate the $\tau$-appearance signals for both long-baseline and near-site experiments, and conclude that the latter is of great use in distinguishing between oscillation and SUSY effects. On the other hand, SUSY can cause a manifold increase in the event rate for wrong-sign muons at a long-baseline setting, thereby providing us with signatures of new physics.Comment: 7 pages LaTeX, 4 ps figures, accepted for publication in Phys. Rev.

Neutrino Interactions at Ultrahigh Energies

We report new calculations of the cross sections for deeply inelastic neutrino-nucleon scattering at neutrino energies between 10^{9}\ev and 10^{21}\ev. We compare with results in the literature and assess the reliability of our predictions. For completeness, we briefly review the cross sections for neutrino interactions with atomic electrons, emphasizing the role of the $W$-boson resonance in $\bar{\nu}_{e}e$ interactions for neutrino energies in the neighborhood of 6.3\pev. Adopting model predictions for extraterrestrial neutrino fluxes from active galactic nuclei, gamma-ray bursters, and the collapse of topological defects, we estimate event rates in large-volume water \v{C}erenkov detectors and large-area ground arrays.Comment: 32 pages, 11 figures, uses RevTeX and boxedep

Testing the solar LMA region with KamLAND data

We investigate the potential of 3 kiloTon-years(kTy) of KamLAND data to further constrain the $\Delta m^2$ and $\tan^2\theta$ values compared to those presently allowed by existing KamLAND and global solar data. We study the extent, dependence and characteristics of this sensitivity in and around the two parts of the LMA region that are currently allowed. Our analysis with 3 kTy simulated spectra shows that KamLAND spectrum data by itself can constrain $\Delta m^2$ with high precision. Combining the spectrum with global solar data further tightens the constraints on allowed values of $\tan^2\theta$ and $\Delta m^2$. We also study the effects of future neutral current data with a total error of 7% from the Sudbury Neutrino Observatory. We find that these future measurements offer the potential of considerable precision in determining the oscillation parameters (specially the mass parameter).Comment: 16 pages, to appear in J Phys.

Physics Potential of the ICAL detector at the India-based Neutrino Observatory (INO)

The upcoming 50 kt magnetized iron calorimeter (ICAL) detector at the India-based Neutrino Observatory (INO) is designed to study the atmospheric neutrinos and antineutrinos separately over a wide range of energies and path lengths. The primary focus of this experiment is to explore the Earth matter effects by observing the energy and zenith angle dependence of the atmospheric neutrinos in the multi-GeV range. This study will be crucial to address some of the outstanding issues in neutrino oscillation physics, including the fundamental issue of neutrino mass hierarchy. In this document, we present the physics potential of the detector as obtained from realistic detector simulations. We describe the simulation framework, the neutrino interactions in the detector, and the expected response of the detector to particles traversing it. The ICAL detector can determine the energy and direction of the muons to a high precision, and in addition, its sensitivity to multi-GeV hadrons increases its physics reach substantially. Its charge identification capability, and hence its ability to distinguish neutrinos from antineutrinos, makes it an efficient detector for determining the neutrino mass hierarchy. In this report, we outline the analyses carried out for the determination of neutrino mass hierarchy and precision measurements of atmospheric neutrino mixing parameters at ICAL, and give the expected physics reach of the detector with 10 years of runtime. We also explore the potential of ICAL for probing new physics scenarios like CPT violation and the presence of magnetic monopoles.Comment: 139 pages, Physics White Paper of the ICAL (INO) Collaboration, Contents identical with the version published in Pramana - J. Physic

Responses of caudal vestibular nucleus neurons of conscious cats to rotations in vertical planes, before and after a bilateral vestibular neurectomy

Abstract Although many previous experiments have considered the responses of vestibular nucleus neurons to rotations and translations of the head, little data are available regarding cells in the caudalmost portions of the vestibular nuclei (CVN), which mediate vestibulo-autonomic responses among other functions. This study examined the responses of CVN neurons of conscious cats to rotations in vertical planes, both before and after a bilateral vestibular neurectomy. None of the units included in the data sample had eye movementrelated activity. In labyrinth-intact animals, some CVN neurons (22%) exhibited graviceptive responses consistent with inputs from otolith organs, but most (55%) had dynamic responses with phases synchronized with stimulus velocity. Furthermore, the large majority of CVN neurons had response vector orientations that were aligned either near the roll or vertical canal planes, and only 18% of cells were preferentially activated by pitch rotations. Sustained head-up rotations of the body provide challenges to the cardiovascular system and breathing, and thus the response dynamics of the large majority of CVN neurons were dissimilar to those of posturally-related autonomic reflexes. These data suggest that vestibular influences on autonomic control mediated by the CVN are more complex than previously envisioned, and likely involve considerable processing and integration of signals by brainstem regions involved in cardiovascular and respiratory regulation. Following a bilateral vestibular neurectomy, CVN neurons regained spontaneous activity within 24 h, and a very few neurons (\10%) responded to vertical tilts \15°in amplitude. These findings indicate that nonlabyrinthine inputs are likely important in sustaining the activity of CVN neurons; thus, these inputs may play a role in functional recovery following peripheral vestibular lesions