ATP gatekeeper of Plasmodium protein kinase may provide the opportunity to develop selective antimalarial drugs with multiple targets

Malaria is one of the most devastating infectious diseases that caused millions of clinical cases annually despite decades of prevention efforts. Recent cases of Plasmodium falciparum resistance against the only remaining class of effective antimalarial (artemisinin) in South East Asia may soon pose a significant threat. Hence, the identification of new antimalarial compounds with a novel mode of action is necessary to curb this problem. Protein kinase has been implicated as a valid target for drug development in diseases such as cancer and diabetes in humans. A similar approach is now recognized for the treatment of protozoan-related disease including malaria. Few Plasmodium protein kinases that are not only crucial for their survival but also have unique structural features have been identified as a potential target for drug development. In this review, studies on antimalarial drug development exploiting the size of Plasmodium protein kinase ATP gatekeeper over the past 15 years are mainly discussed. The ATP-binding site of Plasmodium protein kinases such as Pf CDPK1, Pf CDPK4, Pf PKG, Pf PK7, and Pf PI4K showed great potential for selective and multi-target inhibitions owing to their smaller or unique ATP-gatekeeper amino acid subunits compared to that of human protein kinase. Hence it is a feasible solution to identify a new class of active antimalarial agents with a novel mode of action and longer clinical life-span

Plasmodium falciparum protein kinase as a potential therapeutic target for antimalarial drugs development

Malaria is one of the most dangerous infectious diseases due to its high infection and mortality rates, especially in the tropical belt. Plasmodium falciparum (P. falciparum), the most virulent malaria parasite in humans, was recently reported to develop resistance against the final efficient antimalarial drug, artemisinin. Little is known about the resistance mechanisms, which further complicates the problem as a proper counteraction is unable to be taken. Hence, the understanding of drug mode of action and its molecular target is valuable knowledge that needs to be considered to develop the next generation of antimalarial drugs. P. falciparum protein kinase (Pf PK) is an attractive target for antimalarial chemotherapy due to its vital roles in all P. falciparum life stages. Moreover, overall structural differences and the presence of unique Pf PKs that are absent in human kinome, suggesting specific inhibition of Pf PK without affecting human cells is achievable. To date, at least 86 eukaryotic protein kinases have been identified in P. falciparum kinome, by which less than 40 were validated as potential targets at the erythrocytes stage. In this review, recent progress of the furthest validated Pf PKs; Pf Nek-1, Pf CDPK1, Pf CDPK4, Pf PKG, and Pf CLK-3 will be briefly discussed. © 2020, Malaysian Society for Parasitology. All rights reserved

Relativistic Heavy--Ion Collisions in the Dynamical String--Parton Model

We develop and extend the dynamical string parton model. This model, which is based on the salient features of QCD, uses classical Nambu-Got\=o strings with the endpoints identified as partons, an invariant string breaking model of the hadronization process, and interactions described as quark-quark interactions. In this work, the original model is extended to include a phenomenological quantization of the mass of the strings, an analytical technique for treating the incident nucleons as a distribution of string configurations determined by the experimentally measured structure function, the inclusion of the gluonic content of the nucleon through the introduction of purely gluonic strings, and the use of a hard parton-parton interaction taken from perturbative QCD combined with a phenomenological soft interaction. The limited number of parameters in the model are adjusted to $e^+e^-$ and $p$--$p$ data. Utilizing these parameters, the first calculations of the model for $p$--$A$ and $A$--$A$ collisions are presented and found to be in reasonable agreement with a broad set of data.Comment: 26 pages of text with 23 Postscript figures placed in tex

Leading order determination of the gluon polarisation from DIS events with high-p_T hadron pairs

We present a determination of the gluon polarisation Delta g/g in the nucleon, based on the longitudinal double-spin asymmetry of DIS events with a pair of large transverse-momentum hadrons in the final state. The data were obtained by the COMPASS experiment at CERN using a 160 GeV/c polarised muon beam scattering off a polarised ^6LiD target. The gluon polarisation is evaluated by a Neural Network approach for three intervals of the gluon momentum fraction x_g covering the range 0.04 < x_g < 0.27. The values obtained at leading order in QCD do not show any significant dependence on x_g. Their average is Delta g/g = 0.125 +/- 0.060 (stat.) +/- 0.063 (syst.) at x_g=0.09 and a scale of mu^2 = 3 (GeV/c)^2.Comment: 13 pages, 6 figures and 3 table

Photoproduction of D∗±D^{*\pm} mesons associated with a leading neutron

The photoproduction of $D^{*\pm} (2010)$ mesons associated with a leading neutron has been observed with the ZEUS detector in $ep$ collisions at HERA using an integrated luminosity of 80 pb$^{-1}$. The neutron carries a large fraction, {$x_L>0.2$}, of the incoming proton beam energy and is detected at very small production angles, {$\theta_n<0.8$ mrad}, an indication of peripheral scattering. The $D^*$ meson is centrally produced with pseudorapidity {$|\eta| 1.9$ GeV}, which is large compared to the average transverse momentum of the neutron of 0.22 GeV. The ratio of neutron-tagged to inclusive $D^*$ production is $8.85\pm 0.93({\rm stat.})^{+0.48}_{-0.61}({\rm syst.})\%$ in the photon-proton center-of-mass energy range {$130 <W<280$ GeV}. The data suggest that the presence of a hard scale enhances the fraction of events with a leading neutron in the final state.Comment: 28 pages, 4 figures, 2 table

Observation of isolated high-E_T photons in deep inelastic scattering

First measurements of cross sections for isolated prompt photon production in deep inelastic ep scattering have been made using the ZEUS detector at the HERA electron-proton collider using an integrated luminosity of 121 pb^-1. A signal for isolated photons in the transverse energy and rapidity ranges 5 < E_T^gamma < 10 GeV and -0.7 < eta^gamma < 0.9 was observed for virtualities of the exchanged photon of Q^2 > 35 GeV^2. Cross sections are presented for inclusive prompt photons and for those accompanied by a single jet in the range E_T^jet \geq 6 GeV and -1.5 \leq eta^jet < 1.8. Calculations at order alpha^3alpha_s describe the data reasonably well.Comment: 16 pages, 5 figure

Search for contact interactions, large extra dimensions and finite quark radius in ep collisions at HERA

A search for physics beyond the Standard Model has been performed with high-Q^2 neutral current deep inelastic scattering events recorded with the ZEUS detector at HERA. Two data sets, e^+ p \to e^+ X and e^- p \to e^- X, with respective integrated luminosities of 112 pb^-1 and 16 pb^-1, were analyzed. The data reach Q^2 values as high as 40000 GeV^2. No significant deviations from Standard Model predictions were observed. Limits were derived on the effective mass scale in eeqq contact interactions, the ratio of leptoquark mass to the Yukawa coupling for heavy leptoquark models and the mass scale parameter in models with large extra dimensions. The limit on the quark charge radius, in the classical form factor approximation, is 0.85 10^-16 cm.Comment: 28 pages, 4 figures, accepted for publication in Physics Letters

Isolated tau leptons in events with large missing transverse momentum at HERA

A search for events containing isolated tau leptons and large missing transverse momentum, not originating from the tau decay, has been performed with the ZEUS detector at the electron-proton collider HERA, using 130 pb^-1 of integrated luminosity. A search was made for isolated tracks coming from hadronic tau decays. Observables based on the internal jet structure were exploited to discriminate between tau decays and quark- or gluon-induced jets. Three tau candidates were found, while 0.40 +0.12 -0.13 were expected from Standard Model processes, such as charged current deep inelastic scattering and single W-boson production. To search for heavy-particle decays, a more restrictive selection was applied to isolate tau leptons produced together with a hadronic final state with high transverse momentum. Two candidate events survive, while 0.20 +-0.05 events are expected from Standard Model processes.Comment: 28 pages, 4 figures, 3 tables, accepted by Phys. Lett. B. Updated with minor changes to the text requested by the journal refere

Measurement of beauty production in deep inelastic scattering at HERA

The beauty production cross section for deep inelastic scattering events with at least one hard jet in the Breit frame together with a muon has been measured, for photon virtualities Q^2 > 2 GeV^2, with the ZEUS detector at HERA using integrated luminosity of 72 pb^-1. The total visible cross section is sigma_b-bbar (ep -> e jet mu X) = 40.9 +- 5.7 (stat.) +6.0 -4.4 (syst.) pb. The next-to-leading order QCD prediction lies about 2.5 standard deviations below the data. The differential cross sections are in general consistent with the NLO QCD predictions; however at low values of Q^2, Bjorken x, and muon transverse momentum, and high values of jet transverse energy and muon pseudorapidity, the prediction is about two standard deviations below the data.Comment: 18 pages, 4 figure

Forward jet production in deep inelastic ep scattering and low-x parton dynamics at HERA

Differential inclusive jet cross sections in neutral current deep inelastic ep scattering have been measured with the ZEUS detector. Three phase-space regions have been selected in order to study parton dynamics where the effects of BFKL evolution might be present. The measurements have been compared to the predictions of leading-logarithm parton shower Monte Carlo models and fixed-order perturbative QCD calculations. In the forward region, QCD calculations at order alpha_s^1 underestimate the data up to an order of magnitude at low x. An improved description of the data in this region is obtained by including QCD corrections at order alpha_s^2, which account for the lowest-order t-channel gluon-exchange diagrams, highlighting the importance of such terms in parton dynamics at low x.Comment: 25 pages, 4 figure