Pyrazole compound BPR1P0034 with potent and selective anti-influenza virus activity

<p>Abstract</p> <p>Background</p> <p>Influenza viruses are a major cause of morbidity and mortality around the world. More recently, a swine-origin influenza A (H1N1) virus that is spreading via human-to-human transmission has become a serious public concern. Although vaccination is the primary strategy for preventing infections, influenza antiviral drugs play an important role in a comprehensive approach to controlling illness and transmission. In addition, a search for influenza-inhibiting drugs is particularly important in the face of high rate of emergence of influenza strains resistant to several existing influenza antivirals.</p> <p>Methods</p> <p>We searched for novel anti-influenza inhibitors using a cell-based neutralization (inhibition of virus-induced cytopathic effect) assay. After screening 20,800 randomly selected compounds from a library from ChemDiv, Inc., we found that BPR1P0034 has sub-micromolar antiviral activity. The compound was resynthesized in five steps by conventional chemical techniques. Lead optimization and a structure-activity analysis were used to improve potency. Time-of-addition assay was performed to target an event in the virus life cycle.</p> <p>Results</p> <p>The 50% effective inhibitory concentration (IC₅₀) of BPR1P0034 was 0.42 ± 0.11 μM, when measured with a plaque reduction assay. Viral protein and RNA synthesis of A/WSN/33 (H1N1) was inhibited by BPR1P0034 and the virus-induced cytopathic effects were thus significantly reduced. BPR1P0034 exhibited broad inhibition spectrum for influenza viruses but showed no antiviral effect for enteroviruses and echovirus 9. In a time-of-addition assay, in which the compound was added at different stages along the viral replication cycle (such as at adsorption or after adsorption), its antiviral activity was more efficient in cells treated with the test compound between 0 and 2 h, right after viral infection, implying that an early step of viral replication might be the target of the compound. These results suggest that BPR1P0034 targets the virus during viral uncoating or viral RNA importation into the nucleus.</p> <p>Conclusions</p> <p>To the best of our knowledge, BPR1P0034 is the first pyrazole-based anti-influenza compound ever identified and characterized from high throughput screening to show potent (sub-μM) antiviral activity. We conclude that BPR1P0034 has potential antiviral activity, which offers an opportunity for the development of a new anti-influenza virus agent.</p

Mapping the Routes: An exploration of charges of racism made against the 1970s UK Reclaim the Night marches

This article addresses early charges of racism, made against the original UK Reclaim the Night (RTN) marches in the 1970s. These charges appear to have stuck, and been accepted almost as a truism ever since, being maintained in several academic texts. Using archive materials, and recent, empirical qualitative research with founding RTN activists and participants, I shall investigate the emergence of RTN in the UK in 1977 and the practicalities and influences behind this type of protest. I will also consider possible reasons behind the charges of racism, addressing justifiable critiques and concerns. I will conclude that the specific charges made against the first RTN marches were inaccurate. However, I will also explore possible reasons why concerns about racism surrounded these marches at their formation. © 2014

Status report on emerging photovoltaics

\ua9 2023 Society of Photo-Optical Instrumentation Engineers (SPIE).This report provides a snapshot of emerging photovoltaic (PV) technologies. It consists of concise contributions from experts in a wide range of fields including silicon, thin film, III-V, perovskite, organic, and dye-sensitized PVs. Strategies for exceeding the detailed balance limit and for light managing are presented, followed by a section detailing key applications and commercialization pathways. A section on sustainability then discusses the need for minimization of the environmental footprint in PV manufacturing and recycling. The report concludes with a perspective based on broad survey questions presented to the contributing authors regarding the needs and future evolution of PV

Event-by-event correlations between Λ\Lambda (Λˉ\bar{\Lambda}) hyperon global polarization and handedness with charged hadron azimuthal separation in Au+Au collisions at sNN=27 GeV\sqrt{s_{\text{NN}}} = 27 \text{ GeV} from STAR

Global polarizations ($P$) of $\Lambda$ ($\bar{\Lambda}$) hyperons have been observed in non-central heavy-ion collisions. The strong magnetic field primarily created by the spectator protons in such collisions would split the $\Lambda$ and $\bar{\Lambda}$ global polarizations ($\Delta P = P_{\Lambda} - P_{\bar{\Lambda}} < 0$). Additionally, quantum chromodynamics (QCD) predicts topological charge fluctuations in vacuum, resulting in a chirality imbalance or parity violation in a local domain. This would give rise to an imbalance ($\Delta n = \frac{N_{\text{L}} - N_{\text{R}}}{\langle N_{\text{L}} + N_{\text{R}} \rangle} \neq 0$) between left- and right-handed $\Lambda$ ($\bar{\Lambda}$) as well as a charge separation along the magnetic field, referred to as the chiral magnetic effect (CME). This charge separation can be characterized by the parity-even azimuthal correlator ($\Delta\gamma$) and parity-odd azimuthal harmonic observable ($\Delta a_{1}$). Measurements of $\Delta P$, $\Delta\gamma$, and $\Delta a_{1}$ have not led to definitive conclusions concerning the CME or the magnetic field, and $\Delta n$ has not been measured previously. Correlations among these observables may reveal new insights. This paper reports measurements of correlation between $\Delta n$ and $\Delta a_{1}$, which is sensitive to chirality fluctuations, and correlation between $\Delta P$ and $\Delta\gamma$ sensitive to magnetic field in Au+Au collisions at 27 GeV. For both measurements, no correlations have been observed beyond statistical fluctuations.Comment: 10 pages, 10 figures; paper from the STAR Collaboratio

Search for the Chiral Magnetic Effect in Au+Au collisions at sNN=27\sqrt{s_{_{\rm{NN}}}}=27 GeV with the STAR forward Event Plane Detectors

A decisive experimental test of the Chiral Magnetic Effect (CME) is considered one of the major scientific goals at the Relativistic Heavy-Ion Collider (RHIC) towards understanding the nontrivial topological fluctuations of the Quantum Chromodynamics vacuum. In heavy-ion collisions, the CME is expected to result in a charge separation phenomenon across the reaction plane, whose strength could be strongly energy dependent. The previous CME searches have been focused on top RHIC energy collisions. In this Letter, we present a low energy search for the CME in Au+Au collisions at $\sqrt{s_{_{\rm{NN}}}}=27$ GeV. We measure elliptic flow scaled charge-dependent correlators relative to the event planes that are defined at both mid-rapidity $|\eta|<1.0$ and at forward rapidity $2.1 < |\eta|<5.1$. We compare the results based on the directed flow plane ($\Psi_1$) at forward rapidity and the elliptic flow plane ($\Psi_2$) at both central and forward rapidity. The CME scenario is expected to result in a larger correlation relative to $\Psi_1$ than to $\Psi_2$, while a flow driven background scenario would lead to a consistent result for both event planes[1,2]. In 10-50\% centrality, results using three different event planes are found to be consistent within experimental uncertainties, suggesting a flow driven background scenario dominating the measurement. We obtain an upper limit on the deviation from a flow driven background scenario at the 95\% confidence level. This work opens up a possible road map towards future CME search with the high statistics data from the RHIC Beam Energy Scan Phase-II.Comment: main: 8 pages, 5 figures; supplementary material: 2 pages, 1 figur

Observation of the electromagnetic field effect via charge-dependent directed flow in heavy-ion collisions at the Relativistic Heavy Ion Collider

The deconfined quark-gluon plasma (QGP) created in relativistic heavy-ion collisions enables the exploration of the fundamental properties of matter under extreme conditions. Non-central collisions can produce strong magnetic fields on the order of $10^{18}$ Gauss, which offers a probe into the electrical conductivity of the QGP. In particular, quarks and anti-quarks carry opposite charges and receive contrary electromagnetic forces that alter their momenta. This phenomenon can be manifested in the collective motion of final-state particles, specifically in the rapidity-odd directed flow, denoted as $v_1(\mathsf{y})$. Here we present the charge-dependent measurements of $dv_1/d\mathsf{y}$ near midrapidities for $\pi^{\pm}$, $K^{\pm}$, and $p(\bar{p})$ in Au+Au and isobar ($_{44}^{96}$Ru+$_{44}^{96}$Ru and $_{40}^{96}$Zr+$_{40}^{96}$Zr) collisions at $\sqrt{s_{\rm NN}}=$ 200 GeV, and in Au+Au collisions at 27 GeV, recorded by the STAR detector at the Relativistic Heavy Ion Collider. The combined dependence of the $v_1$ signal on collision system, particle species, and collision centrality can be qualitatively and semi-quantitatively understood as several effects on constituent quarks. While the results in central events can be explained by the $u$ and $d$ quarks transported from initial-state nuclei, those in peripheral events reveal the impacts of the electromagnetic field on the QGP. Our data put valuable constraints on the electrical conductivity of the QGP in theoretical calculations

Hyperon polarization along the beam direction relative to the second and third harmonic event planes in isobar collisions at sNN\sqrt{s_{NN}} = 200 GeV

The polarization of $\Lambda$ and $\bar{\Lambda}$ hyperons along the beam direction has been measured relative to the second and third harmonic event planes in isobar Ru+Ru and Zr+Zr collisions at $\sqrt{s_{NN}}$ = 200 GeV. This is the first experimental evidence of the hyperon polarization by the triangular flow originating from the initial density fluctuations. The amplitudes of the sine modulation for the second and third harmonic results are comparable in magnitude, increase from central to peripheral collisions, and show a mild $p_T$ dependence. The azimuthal angle dependence of the polarization follows the vorticity pattern expected due to elliptic and triangular anisotropic flow, and qualitatively disagree with most hydrodynamic model calculations based on thermal vorticity and shear induced contributions. The model results based on one of existing implementations of the shear contribution lead to a correct azimuthal angle dependence, but predict centrality and $p_T$ dependence that still disagree with experimental measurements. Thus, our results provide stringent constraints on the thermal vorticity and shear-induced contributions to hyperon polarization. Comparison to previous measurements at RHIC and the LHC for the second-order harmonic results shows little dependence on the collision system size and collision energy.Comment: 6 pages, 5 figures, Published in Physical Review Letter

Measurement of Λ4H\rm ^4_{\Lambda}H and Λ4He\rm ^4_{\Lambda}He binding energy in Au+Au collisions at sNN\sqrt{s_\mathrm{NN}} = 3 GeV

Measurements of mass and $\Lambda$ binding energy of $\rm ^4_{\Lambda}H$ and $\rm ^4_{\Lambda}He$ in Au+Au collisions at $\sqrt{s_{_{\rm NN}}}=3$ GeV are presented, with an aim to address the charge symmetry breaking (CSB) problem in hypernuclei systems with atomic number A = 4. The $\Lambda$ binding energies are measured to be $\rm 2.22\pm0.06(stat.) \pm0.14(syst.)$ MeV and $\rm 2.38\pm0.13(stat.) \pm0.12(syst.)$ MeV for $\rm ^4_{\Lambda}H$ and $\rm ^4_{\Lambda}He$, respectively. The measured $\Lambda$ binding-energy difference is $\rm 0.16\pm0.14(stat.)\pm0.10(syst.)$ MeV for ground states. Combined with the $\gamma$-ray transition energies, the binding-energy difference for excited states is $\rm -0.16\pm0.14(stat.)\pm0.10(syst.)$ MeV, which is negative and comparable to the value of the ground states within uncertainties. These new measurements on the $\Lambda$ binding-energy difference in A = 4 hypernuclei systems are consistent with the theoretical calculations that result in $\rm \Delta B_{\Lambda}^4(1_{exc}^{+})\approx -\Delta B_{\Lambda}^4(0_{g.s.}^{+})<0$ and present a new method for the study of CSB effect using relativistic heavy-ion collisions.Comment: 8 pages, 5 figure

Elliptic Flow of Heavy-Flavor Decay Electrons in Au+Au Collisions at sNN\sqrt{s_{_{\rm NN}}} = 27 and 54.4 GeV at RHIC

We report on new measurements of elliptic flow ($v_2$) of electrons from heavy-flavor hadron decays at mid-rapidity ($|y|<0.8$) in Au+Au collisions at $\sqrt{s_{_{\rm NN}}}$ = 27 and 54.4 GeV from the STAR experiment. Heavy-flavor decay electrons ($e^{\rm HF}$) in Au+Au collisions at $\sqrt{s_{_{\rm NN}}}$ = 54.4 GeV exhibit a non-zero $v_2$ in the transverse momentum ($p_{\rm T}$) region of $p_{\rm T}<$ 2 GeV/$c$ with the magnitude comparable to that at $\sqrt{s_{_{\rm NN}}}=200$ GeV. The measured $e^{\rm HF}$ $v_2$ at 54.4 GeV is also consistent with the expectation of their parent charm hadron $v_2$ following number-of-constituent-quark scaling as other light and strange flavor hadrons at this energy. These suggest that charm quarks gain significant collectivity through the evolution of the QCD medium and may reach local thermal equilibrium in Au+Au collisions at $\sqrt{s_{_{\rm NN}}}=54.4$ GeV. The measured $e^{\rm HF}$ $v_2$ in Au+Au collisions at $\sqrt{s_{_{\rm NN}}}=$ 27 GeV is consistent with zero within large uncertainties. The energy dependence of $v_2$ for different flavor particles ($\pi,\phi,D^{0}/e^{\rm HF}$) shows an indication of quark mass hierarchy in reaching thermalization in high-energy nuclear collisions.Comment: 12 pages, 7 figures, 1 tabl

Measurement of electrons from open heavy-flavor hadron decays in Au+Au collisions at sNN=200\sqrt{s_{\rm NN}}=200 GeV with the STAR detector

We report a new measurement of the production of electrons from open heavy-flavor hadron decays (HFEs) at mid-rapidity ($|y|<$ 0.7) in Au+Au collisions at $\sqrt{s_{\rm NN}}=200$ GeV. Invariant yields of HFEs are measured for the transverse momentum range of $3.5 < p_{\rm T} < 9$ GeV/$c$ in various configurations of the collision geometry. The HFE yields in head-on Au+Au collisions are suppressed by approximately a factor of 2 compared to that in $p$+$p$ collisions scaled by the average number of binary collisions, indicating strong interactions between heavy quarks and the hot and dense medium created in heavy-ion collisions. Comparison of these results with models provides additional tests of theoretical calculations of heavy quark energy loss in the quark-gluon plasma