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England, D.

Publications and source records attributed to England, D..

2 recordsLinked to original sources
bioRxiv2024

Imaging Ultraweak Photon Emission from Living and Dead Mice and from Plants under Stress

The phenomenon of biological ultraweak photon emission (UPE), that is, extremely low-intensity emission (10 - 103 photons/cm2/sec) in the spectral range of 200 - 1000 nm, has been observed in all living systems that have been examined. Here we report experiments that exemplify the ability of novel imaging systems to detect variations in UPE for a set of physiologically important scenarios. We use EMCCD and CCD cameras to capture single visible-wavelength photons with low noise and quantum efficiencies higher than 90%. Our investigation reveals significant contrast between the UPE from live vs. dead mice. In plants we observed that an increase in temperature and injuries both caused an increase in UPE intensity. Moreover, chemical treatments modified the UPE emission characteristics of plants, particularly the application of an anesthetic (benzocaine) to injury, which showed the highest emission among the compounds tested. As a result, UPE imaging provides the possibility of non-invasive label-free imaging of vitality in animals and the responses of plants to stress.

biophysics↗
bioRxiv2024

A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo

The Plasmodium falciparum cytoplasmic tyrosine tRNA synthetase (PfTyrRS) is an attractive drug target that is susceptible to reaction-hijacking by AMP-mimicking nucleoside sulfamates. We previously identified an exemplar pyrazolopyrimidine ribose sulfamate, ML901, as a potent pro-inhibitor of PfTyrRS. Here we examined the stage specificity of action of ML901, showing very good activity against the schizont stage, but lower trophozoite stage activity. We explored a series of ML901 analogues and identified ML471, which exhibits improved potency against trophozoites and enhanced selectivity against a human cell line. Additionally, it has no inhibitory activity against human ubiquitin-activating enzyme (UAE) in vitro. ML471 exhibits low nanomolar activity against asexual blood stage P. falciparum and potent activity against liver stage parasites, gametocytes and transmissible gametes. It is fast-acting and exhibits a long in vivo half-life. ML471 is well-tolerated and shows single dose oral efficacy in the SCID mouse model of P. falciparum malaria. We confirm that ML471 is a pro-inhibitor that is converted into a tight binding Tyr-ML471 conjugate by the PfTyrRS enzyme. A crystal structure of the PfTyrRS/ Tyr-ML471 complex offers insights into improved potency, while molecular docking into UAE provides a rationale for improved selectivity.

biochemistry↗