Leishmania donovani express two members of the equilibrative nucleoside transporter family; LdNT1 encoded by two closely related and linked genes, LdNT1.1 and LdNT1.2, that transport adenosine and pyrimidine nucleosides and LdNT2 that transports inosine and guanosine exclusively. LdNT1.1, LdNT1.2, and LdNT2 have been expressed in Xenopus laevis oocytes and found to be electrogenic in the presence of nucleoside ligands for which they mediate transport. Further analysis revealed that ligand uptake and transport currents through LdNT1-type transporters are proton-dependent. In addition to the flux of protons that is coupled to the transport reaction, LdNT1 transporters mediate a variable constitutive proton conductance that is blocked by substrates and dipyridamole. Surprisingly, LdNT1.1 and LdNT1.2 exhibit different electrogenic properties, despite their close sequence homology. This electrophysiological study provides the first demonstration that members of the equilibrative nucleoside transporter family can be electrogenic and establishes that these three permeases, unlike their mammalian counterparts, are probably concentrative rather than facilitative transporters.Leishmania donovani is a protozoan parasite that causes visceral leishmaniasis, a devastating and often fatal disease in humans. The parasite exhibits a digenetic life cycle; the extracellular, flagellated, and motile promastigote that resides within the insect vector, members of the phlebotomine sandfly family, and the intracellular, aflagellar, and nonmotile amastigote that exists within the phagolysosome of macrophages and other reticuloendothelial cells of the infected mammalian host. The drugs used to treat visceral leishmaniasis have been empirically derived and are toxic, require prolonged and multiple administrations, and are often ineffective. The toxicity can be ascribed to the lack of target specificity within the parasite. Thus, the need for more efficacious and specific drugs is acute.The design of selective antiparasitic drugs depends on the exploitation of fundamental biochemical differences between parasite and host. Perhaps the most remarkable metabolic discrepancy between protozoan parasites and their human host is that the former are incapable of synthesizing the purine ring de novo (1). Thus, all protozoan parasites studied to date have evolved a unique series of purine salvage enzymes that enable parasites to scavenge purines from their host. Purine acquisition by the parasite is initiated by the translocation of extracellular purines across the parasite cell surface membranes, a process that is mediated by nutritionally indispensable nucleoside and nucleobase transporters.Genetic and biochemical investigations (2, 3) have demonstrated that L. donovani express two nucleoside transporter activities of nonoverlapping ligand specificities; LdNT1, which recognizes adenosine and pyrimidine nucleosides, and LdNT2, which mediates the transport of inosine and guanosine. Subsequently, the genes encoding LdNT1 (4) and LdNT2 (5) were isolat...
This Article analyzes the probabilistic and epistemological underpinnings of the burden of proof doctrine. We show that this doctrine is best understood as instructing factfinders to determine which of the parties' conflicting stories makes most sense in terms of coherence, consilience, causality, and evidential coverage. By applying this method, factfinders should try-and will often succeed-to establish the truth, rather than a statistical surrogate of the truth, while securing the appropriate allocation of the risk of error. Descriptively, we argue that this understanding of the doctrine-the "relative plausibility theory"-corresponds to our courts' practice. Prescriptively, we argue that the relative-plausibility method is operationally superior to factfinding that relies on mathematical probability. This method aligns with people's natural reasoning and common sense, avoids paradoxes engendered by mathematical probability, and seamlessly integrates with the rules of substantive law that guide individuals' primary conduct and determine liabilities and entitlements. We substantiate this claim by juxtaposing the extant doctrine against two recent contributions to evidence theory: Professor Louis Kaplow's proposal that the burden of proof should be modified to track the statistical distributions of harms and benefits associated with relevant primary activities; and Professor Edward Cheng's model that calls on factfinders to make their decisions by using numbers instead of words. Specifically, we demonstrate that both models suffer from serious conceptual problems and are not feasible operationally. The extant burden of proof doctrine, we conclude, works well and requires no far-reaching reforms.
This Article develops a consequentialist game-theoretic perspective for understanding the right to silence. Professors Seidmann and Stein reveal that the conventional perception of the right to silencethat it impedes the search for truth and thus helps only criminalsis mistaken. Professors Seidmann and Stein demonstrate that the right to silence can help triers of fact to distinguish between innocent and guilty suspects and defendants. They argue that a guilty suspect's self-interested response to questioning can impose externalities, in the form of wrongful conviction, on innocent suspects and defendants who tell the truth but cannot corroborate their responses. Absent the right to silence, guilty suspects and defendants would make false exculpatory statements if they believed that their lies were unlikely to be exposed. Aware of these incentives, triers of fact would rationally discount the probative value of uncorroborated exculpatory statements at the expense of innocent defendants who could not corroborate their true exculpatory statements. Because the right to silence is available, innocent defendants still tell the truth while guilty defendants may rationally exercise the right. Thus, guilty defendants do not pool with innocent defendants by lying, and as a result, triers of fact do not wrongfully convict innocent defendants. Professors Seidmann and Stein contend that the existing empirical data support their game-theoretic analysis. Furthermore, In memory of Ian Molho.
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