Targeting proteases and proteolytic processing of unusual N-terminal extensions of Plasmodium proteins: parasite peculiarity

More than sesquicentennial years of malarial research, however the unique malarial parasite, Plasmodium still bewilders us with its atypical characteristic features. Elimination strategies, deeper knowledge of the parasite biology and pathways can help combat this global health concern that affects ∼250 million people annually. In this review, we unveil an unusual phenomenon observed in the parasite proteome, N-terminal extensions in proteins and highlight that the proteases that may be involved in their processing events, are potential candidates to target this pathogen. Plasmodium encodes larger proteins as compared to its eukaryotic counterparts with homology regions present in the C-terminus of the protein. In contrast, the function of unusual extensions in the N-terminus remains mostly elusive. This novelty observed in Plasmodium proteins is collated here with a focus on replication proteins. The plausible functions and prevalence of these extensions, despite the reduction in genome size, through the parasite evolution are also mentioned. We hypothesize that these extensions, propagated via the energy consuming cellular processes in the otherwise host-dependent obligate parasite, are beneficial to the parasite in ways that are yet to be explored. Consequently, targeting the proteolytic processing of these proteins and the involved proteases would serve as a new drug development regimen to tackle the emerging resistance in parasites to existing antimalarials

Phase diffusion and fluctuations in a dissipative Bose-Josephson junction

We analyze the phase diffusion, quantum fluctuations and their spectral features of an one-dimensional Bose-Josephson junction (BJJ) coupled to a bosonic heat bath. We show the dependence of the phase diffusion coefficient on the on-site interaction parameter $U$ and the temperature in zero-phase and $\pi$-phase modes. We find that in the $\pi$-phase mode, the phase diffusion co-efficient as a function of $U$ decreases so long as $U$ is below a critical value while it increases above the critical value. This criticality of on-site interaction reflects a transition between Josephson oscillation and macroscopic quantum self-trapping (MQST) regime. Based on the thermal canonical Wigner distribution, we calculate the coherence factor to understand its dependence on temperature and on-site interaction energy in Josephson oscillation and MQST regime. Furthermore, we discuss coherent and incoherent spectral properties in connection with the fluctuations of the relative phase and the population imbalance in both zero and $\pi$-phase modes from weak to strong dissipation regime

The effects of trap-confinement and interatomic interactions on Josephson effects and macroscopic quantum self-trapping for a Bose-Einstein Condensate

We theoretically study the effects of trap-confinement and interatomic interactions on Josephson oscillations (JO) and macroscopic quantum self-trapping (MQST) for a Bose-Einstein condensate (BEC) confined in a trap which has a symmetric double-well (DW) potential along z-axis and 2D harmonic potentials along x- and y-axis. We consider three types of model interaction potentials: contact, long-range dipolar and finite-range potentials. Our results show that by changing the aspect ratio between the axial and radial trap sizes, one can induce a transition from JO to MQST for contact interactions with a small scattering length. For long-range dipolar interatomic interactions, we analyze transition from Rabi to Josephson regime and Josephson to MQST regime by changing the aspect ratio of the trap for a particular dipolar orientation. For a finite-range interaction, we study the effects of relatively large scattering length and effective range on JO and MQST. We show that JO and MQST are possible even if scattering length is relatively large, particularly near a narrow Feshbach resonance due to the finite-range effects

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

Epstein-Barr Virus Nuclear Antigen 3C Facilitates G1-S Transition by Stabilizing and Enhancing the Function of Cyclin D1

EBNA3C, one of the Epstein-Barr virus (EBV)-encoded latent antigens, is essential for primary B-cell transformation. Cyclin D1, a key regulator of G1 to S phase progression, is tightly associated and aberrantly expressed in numerous human cancers. Previously, EBNA3C was shown to bind to Cyclin D1 in vitro along with Cyclin A and Cyclin E. In the present study, we provide evidence which demonstrates that EBNA3C forms a complex with Cyclin D1 in human cells. Detailed mapping experiments show that a small N-terminal region which lies between amino acids 130–160 of EBNA3C binds to two different sites of Cyclin D1- the N-terminal pRb binding domain (residues 1–50), and C-terminal domain (residues 171–240), known to regulate Cyclin D1 stability. Cyclin D1 is short-lived and ubiquitin-mediated proteasomal degradation has been targeted as a means of therapeutic intervention. Here, we show that EBNA3C stabilizes Cyclin D1 through inhibition of its poly-ubiquitination, and also increases its nuclear localization by blocking GSK3β activity. We further show that EBNA3C enhances the kinase activity of Cyclin D1/CDK6 which enables subsequent ubiquitination and degradation of pRb. EBNA3C together with Cyclin D1-CDK6 complex also efficiently nullifies the inhibitory effect of pRb on cell growth. Moreover, an sh-RNA based strategy for knock-down of both cyclin D1 and EBNA3C genes in EBV transformed lymphoblastoid cell lines (LCLs) shows a significant reduction in cell-growth. Based on these results, we propose that EBNA3C can stabilize as well as enhance the functional activity of Cyclin D1 thereby facilitating the G1-S transition in EBV transformed lymphoblastoid cell lines

Dynamical phase diagram of a one dimensional Bose gas in a box with a tunable weak-link: from Bose-Josephson oscillations to shock waves

International audienceWe study the dynamics of one-dimensional bosons trapped in a box potential, in the presence of a barrier creating a tunable weak-link, thus realizing a one dimensional Bose Josephson junction. By varying the initial population imbalance and the barrier height we evidence different dynamical regimes. In particular we show that at large barriers a two mode model captures accurately the dynamics, while for low barriers the dynamics involves dispersive shock waves and solitons. We study a quench protocol that can be readily implemented in experiments and show that self-trapping resonances can occur. This phenomenon can be understood qualitatively within the two-mode model