A new empirical challenge for local theories of consciousness

Local theories of consciousness state that one is conscious of a feature if it is adequately represented and processed in sensory brain areas, given some background conditions. We challenge the core prediction of local theories based on recently discovered long-lasting postdictive effects demonstrating that features can be represented for hundreds of milliseconds in perceptual areas without being consciously perceived. Unlike previous empirical data aimed against local theories, proponents of local theories cannot explain these effects away by conjecturing that subjects are phenomenally conscious of features that they cannot report. Only a strong and counterintuitive version of this claim can account for long-lasting postdictive effects. Although possible, we argue that adopting this strong version of the “overflow hypothesis” would have the effect of nullifying the weight of the evidence taken to support local theories of consciousness in the first place. We also discuss several alternative explanations that proponents of local theories could offer

The protein-phosphatome of the human malaria parasite Plasmodium falciparum

<p>Abstract</p> <p>Background</p> <p>Malaria, caused by the parasitic protist <it>Plasmodium falciparum</it>, represents a major public health problem in the developing world. The <it>P. falciparum </it>genome has been sequenced, which provides new opportunities for the identification of novel drug targets. We report an exhaustive analysis of the <it>P. falciparum </it>genomic database (PlasmoDB) aimed at identifying and classifying all protein phosphatases (PP) in this organism.</p> <p>Results</p> <p>Using a variety of bioinformatics tools, we identified 27 malarial putative PP sequences within the four major established PP families, plus 7 sequences that we predict to dephosphorylate "non-protein" substrates. We constructed phylogenetic trees to position these sequences relative to PPs from other organisms representing all major eukaryotic phyla except Cercozoans (for which no full genome sequence is available). Predominant observations were: (i) <it>P. falciparum </it>possessed the smallest phosphatome of any of the organisms investigated in this study; (ii) no malarial PP clustered with the tyrosine-specific subfamily of the PTP group (iii) a cluster of 7 closely related members of the PPM/PP2C family is present, and (iv) some <it>P. falciparum </it>protein phosphatases are present in clades lacking any human homologue.</p> <p>Conclusion</p> <p>The considerable phylogenetic distance between Apicomplexa and other Eukaryotes is reflected by profound divergences between the phosphatome of malaria parasites and those of representative organisms from all major eukaryotic phyla, which might be exploited in the context of efforts for the discovery of novel targets for antimalarial chemotherapy.</p

Life cycle studies of the hexose transporter of Plasmodium species and genetic validation of their essentiality

A Plasmodium falciparum hexose transporter (PfHT) has previously been shown to be a facilitative glucose and fructose transporter. Its expression in Xenopus laevis oocytes and the use of a glucose analogue inhibitor permitted chemical validation of PfHT as a novel drug target. Following recent re-annotations of the P. falciparum genome, other putative sugar transporters have been identified. To investigate further if PfHT is the key supplier of hexose to P. falciparum and to extend studies to different stages of Plasmodium spp., we functionally analysed the hexose transporters of both the human parasite P. falciparum and the rodent parasite Plasmodium berghei using gene targeting strategies. We show here the essential function of pfht for the erythrocytic parasite growth as it was not possible to knockout pfht unless the gene was complemented by an episomal construct. Also, we show that parasites are rescued from the toxic effect of a glucose analogue inhibitor when pfht is overexpressed in these transfectants. We found that the rodent malaria parasite orthologue, P. berghei hexose transporter (PbHT) gene, was similarly refractory to knockout attempts. However, using a single cross-over transfection strategy, we generated transgenic P. berghei parasites expressing a PbHT–GFP fusion protein suggesting that locus is amenable for gene targeting. Analysis of pbht-gfp transgenic parasites showed that PbHT is constitutively expressed through all the stages in the mosquito host in addition to asexual stages. These results provide genetic support for prioritizing PfHT as a target for novel antimalarials that can inhibit glucose uptake and kill parasites, as well as unveiling the expression of this hexose transporter in mosquito stages of the parasite, where it is also likely to be critical for survival

Duet Lectorials: An Engaging Approach to Interdisciplinary Teaching

[EN] Duet Lectorials were delivered to third-year students undertaking their final ‘cap-stone’ unit by two experts straddling two inter-related but distinct biomedical disciplines. This interdisciplinary teaching approach was introduced for two reasons: firstly, to address a gap in integrated learning at the interface between biomedical disciplines; and secondly, to support non- teaching focused, research experts, in the engaging delivery of lectures. Compared with traditional lecture delivery, students who had received Duet Lectorials reported an increase in their enjoyment of learning, a greater interest and engagement with the subject content, and, most importantly, improved in-depth understanding of the topic through an integrated perspective of the two disciplines. This positive outcome in student learning was further validated by improved performance in objective assessment tasks. Lecturers delivering Duet Lectorials reported a deepening of their own interdisciplinary knowledge that stimulated their enjoyment of teaching. Thus, interdisciplinary teaching using interactive Duet Lectorials emerges as a powerful approach to improve both student and teacher engagement and learning in the classroom, and brings a strong contribution to breaking the discipline-specific “silo” mentality in the teaching of complex aspects of biomedical sciences.http://ocs.editorial.upv.es/index.php/HEAD/HEAD18Slattery, R.; Taylor, R.; Doerig, C. (2018). Duet Lectorials: An Engaging Approach to Interdisciplinary Teaching. Editorial Universitat Politècnica de València. 951-959. https://doi.org/10.4995/HEAD18.2018.8125OCS95195

Building perception block by block: a response to Fekete et al

Is consciousness a continuous stream, or do percepts occur only at certain moments of time? This age-old question is still under debate. Both positions face difficult problems, which we proposed to overcome with a 2-stage model, where unconscious processing continuously integrates information before a discrete, conscious percept occurs. Recently, Fekete et al. criticized our model. Here, we show that, contrary to their proposal, simple sliding windows cannot explain apparent motion and related phenomena within a continuous framework, and that their supervenience argument only holds true for qualia realists, a philosophical position we do not adopt

First-Person Experience Cannot Rescue Causal Structure Theories from the Unfolding Argument

We recently put forward an argument, the Unfolding Argument (UA), that integrated information theory (IIT) and other causal structure theories are either already falsified or unfalsifiable, which provoked significant criticism. It seems that we and the critics agree that the main question in this debate is whether first-person experience, independent of third-person data, is a sufficient foundation for theories of consciousness. Here, we argue that pure first-person experience cannot be a scientific foundation for IIT because science relies on taking measurements, and pure first-person experience is not measurable except through reports, brain activity, and the relationship between them. We also argue that pure first-person experience cannot be taken as ground truth because science is about backing up theories with data, not about asserting that we have ground truth independent of data. Lastly, we explain why no experiment based on third-person data can test IIT as a theory of consciousness. IIT may be a good theory of something, but not of consciousness. We conclude by exposing a deeper reason for the above conclusions: IIT’s consciousness is by construction fully dissociated from any measurable thing and, for this reason, IIT implies that both the level and content of consciousness are epiphenomenal, with no causal power. IIT and other causal structure theories end up in a form of dissociative epiphenomenalism, in which we cannot even trust reports about first-person experiences. But reports about first-person experiences are taken as ground truth and the foundation for IIT’s axioms. Therefore, accepting IIT leads to rejecting its own axioms. We also respond to several other criticisms against the UA

SAM domain-dependent activity of PfTKL3, an essential tyrosine kinase-like kinase of the human malaria parasite Plasmodium falciparum

Over the last decade, several protein kinases inhibitors have reached the market for cancer chemotherapy. The kinomes of pathogens represent potentially attractive targets in infectious diseases. The functions of the majority of protein kinases of Plasmodium falciparum, the parasitic protist responsible for the most virulent form of human malaria, remain unknown. Here we present a thorough characterisation of PfTKL3 (PF13_0258), an enzyme that belongs to the tyrosine kinase-like kinase (TKL) group. We demonstrate by reverse genetics that PfTKL3 is essential for asexual parasite proliferation in human erythrocytes. PfTKL3 is expressed in both asexual and gametocytes stages, and in the latter the protein co-localises with cytoskeleton microtubules. Recombinant PfTKL3 displays in vitro autophosphorylation activity and is able to phosphorylate exogenous substrates, and both activities are dramatically dependent on the presence of an N-terminal "sterile α-motif” domain. This study identifies PfTKL3 as a validated drug target amenable to high-throughput screenin

The Toxoplasma gondii plastid replication and repair enzyme complex, PREX

A plastid-like organelle, the apicoplast, is essential to the majority of medically and veterinary important apicomplexan protozoa including Toxoplasma gondii and Plasmodium. The apicoplast contains multiple copies of a 35 kb genome, the replication of which is dependent upon nuclear-encoded proteins that are imported into the organelle. In P. falciparum an unusual multi-functional gene, pfprex, was previously identified and inferred to encode a protein with DNA primase, DNA helicase and DNA polymerase activities. Herein, we report the presence of a prex orthologue in T. gondii. The protein is predicted to have a bi-partite apicoplast targeting sequence similar to that demonstrated on the PfPREX polypeptide, capable of delivering marker proteins to the apicoplast. Unlike the P. falciparum gene that is devoid of introns, the T. gondii prex gene carries 19 introns, which are spliced to produce a contiguous mRNA. Bacterial expression of the polymerase domain reveals the protein to be active. Consistent with the reported absence of a plastid in Cryptosporidium species, in silico analysis of their genomes failed to demonstrate an orthologue of prex. These studies indicate that prex is conserved across the plastid-bearing apicomplexans and may play an important role in the replication of the plastid genome

Hard Criteria for Empirical Theories of Consciousness

Consciousness is now a well-established field of empirical research. A large body of experimental results has been accumulated and is steadily growing. In parallel, many Theories of Consciousness (ToCs) have been proposed. These theories are diverse in nature, ranging from computational to neurophysiological and quantum theoretical approaches. This contrasts with other fields of natural science, which host a smaller number of competing theories. We suggest that one reason for this abundance of extremely different theories may be the lack of stringent criteria specifying how empirical data constrains ToCs. First, we argue that consciousness is a well-defined topic from an empirical point of view and motivate a purely empirical stance on the quest for consciousness. Second, we present a checklist of criteria that, we propose, empirical ToCs need to cope with. Third, we review 13 of the most influential ToCs and subject them to the criteria. Our analysis helps to situate these different ToCs in the theoretical landscape and sheds light on their strengths and weaknesses from a strictly empirical point of view

An evolutionary perspective on the kinome of malaria parasites

Malaria parasites belong to an ancient lineage that diverged very early from the main branch of eukaryotes. The approximately 90-member plasmodial kinome includes a majority of eukaryotic protein kinases that clearly cluster within the AGC, CMGC, TKL, CaMK and CK1 groups found in yeast, plants and mammals, testifying to the ancient ancestry of these families. However, several hundred millions years of independent evolution, and the specific pressures brought about by first a photosynthetic and then a parasitic lifestyle, led to the emergence of unique features in the plasmodial kinome. These include taxon-restricted kinase families, and unique peculiarities of individual enzymes even when they have homologues in other eukaryotes. Here, we merge essential aspects of all three malaria-related communications that were presented at the Evolution of Protein Phosphorylation meeting, and propose an integrated discussion of the specific features of the parasite's kinome and phosphoproteome