Reward prediction error and declarative memory

Learning based on reward prediction error (RPE) was originally proposed in the context of nondeclarative memory. We postulate that RPE may support declarative memory as well. Indeed, recent years have witnessed a number of independent empirical studies reporting effects of RPE on declarative memory. We provide a brief overview of these studies, identify emerging patterns, and discuss open issues such as the role of signed versus unsigned RPEs in declarative learning

Efficient computation of rank probabilities in posets

As the title of this work indicates, the central theme in this work is the computation of rank probabilities of posets. Since the probability space consists of the set of all linear extensions of a given poset equipped with the uniform probability measure, in first instance we develop algorithms to explore this probability space efficiently. We consider in particular the problem of counting the number of linear extensions and the ability to generate extensions uniformly at random. Algorithms based on the lattice of ideals representation of a poset are developed. Since a weak order extension of a poset can be regarded as an order on the equivalence classes of a partition of the given poset not contradicting the underlying order, and thus as a generalization of the concept of a linear extension, algorithms are developed to count and generate weak order extensions uniformly at random as well. However, in order to reduce the inherent complexity of the problem, the cardinalities of the equivalence classes is fixed a priori. Due to the exponential nature of these algorithms this approach is still not always feasible, forcing one to resort to approximative algorithms if this is the case. It is well known that Markov chain Monte Carlo methods can be used to generate linear extensions uniformly at random, but no such approaches have been used to generate weak order extensions. Therefore, an algorithm that can be used to sample weak order extensions uniformly at random is introduced. A monotone assignment of labels to objects from a poset corresponds to the choice of a weak order extension of the poset. Since the random monotone assignment of such labels is a step in the generation process of random monotone data sets, the ability to generate random weak order extensions clearly is of great importance. The contributions from this part therefore prove useful in e.g. the field of supervised classification, where a need for synthetic random monotone data sets is present. The second part focuses on the ranking of the elements of a partially ordered set. Algorithms for the computation of the (mutual) rank probabilities that avoid having to enumerate all linear extensions are suggested and applied to a real-world data set containing pollution data of several regions in Baden-Württemberg (Germany). With the emergence of several initiatives aimed at protecting the environment like the REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) project of the European Union, the need for objective methods to rank chemicals, regions, etc. on the basis of several criteria still increases. Additionally, an interesting relation between the mutual rank probabilities and the average rank probabilities is proven. The third and last part studies the transitivity properties of the mutual rank probabilities and the closely related linear extension majority cycles or LEM cycles for short. The type of transitivity is translated into the cycle-transitivity framework, which has been tailor-made for characterizing transitivity of reciprocal relations, and is proven to be situated between strong stochastic transitivity and a new type of transitivity called delta*-transitivity. It is shown that the latter type is situated between strong stochastic transitivity and a kind of product transitivity. Furthermore, theoretical upper bounds for the minimum cutting level to avoid LEM cycles are found. Cutting levels for posets on up to 13 elements are obtained experimentally and a theoretic lower bound for the cutting level to avoid LEM cycles of length 4 is computed. The research presented in this work has been published in international peer-reviewed journals and has been presented on international conferences. A Java implementation of several of the algorithms presented in this work, as well as binary files containing all posets on up to 13 elements with LEM cycles, can be downloaded from the website http://www.kermit.ugent.be

Spontaneous eyeblinks during breaking continuous flash suppression are associated with increased detection times

An eyeblink has a clear effect on low-level information processing because it temporarily occludes all visual information. Recent evidence suggests that eyeblinks can also modulate higher level processes (e.g. attentional resources), and vice versa. Despite these putative effects on different levels of information processing, eyeblinks are typically neglected in vision and in consciousness research. The main aim of this study was to investigate the timing and the effect of eyeblinks in an increasingly popular paradigm in consciousness research, namely breaking continuous flash suppression (b-CFS). Results show that participants generally refrain from blinking during a trial, that is, when they need to detect a suppressed stimulus. However, when they do blink during a trial, we observed a sharp increase in suppression time. This suggests that one needs to control for blinking when comparing detection times between conditions that could elicit phasic changes in blinking.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Annotation of novel neuropeptide precursors in the migratory locust based on transcript screening of a public EST database and mass spectrometry

BACKGROUND: For holometabolous insects there has been an explosion of proteomic and peptidomic information thanks to large genome sequencing projects. Heterometabolous insects, although comprising many important species, have been far less studied. The migratory locust Locusta migratoria, a heterometabolous insect, is one of the most infamous agricultural pests. They undergo a well-known and profound phase transition from the relatively harmless solitary form to a ferocious gregarious form. The underlying regulatory mechanisms of this phase transition are not fully understood, but it is undoubtedly that neuropeptides are involved. However, neuropeptide research in locusts is hampered by the absence of genomic information. RESULTS: Recently, EST (Expressed Sequence Tag) databases from Locusta migratoria were constructed. Using bioinformatical tools, we searched these EST databases specifically for neuropeptide precursors. Based on known locust neuropeptide sequences, we confirmed the sequence of several previously identified neuropeptide precursors (i.e. pacifastin-related peptides), which consolidated our method. In addition, we found two novel neuroparsin precursors and annotated the hitherto unknown tachykinin precursor. Besides one of the known tachykinin peptides, this EST contained an additional tachykinin-like sequence. Using neuropeptide precursors from Drosophila melanogaster as a query, we succeeded in annotating the Locusta neuropeptide F, allatostatin-C and ecdysis-triggering hormone precursor, which until now had not been identified in locusts or in any other heterometabolous insect. For the tachykinin precursor, the ecdysis-triggering hormone precursor and the allatostatin-C precursor, translation of the predicted neuropeptides in neural tissues was confirmed with mass spectrometric techniques. CONCLUSION: In this study we describe the annotation of 6 novel neuropeptide precursors and the neuropeptides they encode from the migratory locust, Locusta migratoria. By combining the manual annotation of neuropeptides with experimental evidence provided by mass spectrometry, we demonstrate that the genes are not only transcribed but also translated into precursor proteins. In addition, we show which neuropeptides are cleaved from these precursor proteins and how they are post-translationally modified

Mode of Action of Farnesol, the “Noble Unknown” in Particular in Ca2+ Homeostasis, and Its Juvenile Hormone-Esters in Evolutionary Retrospect

Farnesol, the sesquiterpenoid precursor of insect juvenile hormones (JH) that itself has JH activity, existed already long before animals and their hormones came into being. Although it is omnipresent in all eukaryotes, this molecule remains a “noble unknown” in cell physiology. It is neither documented as a hormone nor as another type of signaling molecule. To date, its function as an intermediate in the synthesis of squalene-cholesterol-steroids in chordates/vertebrates, and of the insect/arthropod JHs, esters of farnesol, in the mevalonate biosynthetic pathway is assumed to be the only one. This assumption neglects that already two decades ago, farnesol has been shown to be a potent endogenous inhibitor of N-type voltage-gated Ca2+ channels in some mammalian cell types. The tandem mevalonate pathway and Ca2+ channels originated early in eukaryotic evolution, and has since been well conserved, “promoting” it as a ubiquitous player in Ca2+ homeostasis in all eukaryotes. This paper accentuates how this drastic change in thinking gained momentum after the discovery by Paroulek and Sláma that the huge amounts of JH I in male accessory glands of the Cecropia moth, are actually synthesized in these glands themselves and not in the corpora allata, the hitherto assumed unique synthesis site of such compounds. In addition, MAG-JHs have no hormonal- but an exocrine function. Here we hypothesize that MAG-JHs may function in protecting the spermatozoa against toxic Ca2+ concentrations, and in enabling their flagellum to undulate. They may do so by acting through membrane receptors. Our novel paradigm assigns to farnesol/JHs a function of flexible hydrophobic molecular valves for restricting untimely Ca2+-passage through some types of canonical Ca2+channels, using covalently bound farnesyl- or geranyl-geranyl group attachment as well as GPCRs-G proteins all containing a prenyl group. The high rotatable bond count, and their horseshoe-shape are instrumental to their valve function. In our paradigm, Met/Tai and Gce, to date generally thought to be the (only) functional (nuclear) receptors for JHs, are classified as probable Ca2+-sensitive transcription factors. Some theoretical and practical considerations for possible applications in a medical context will be discussed

Flip-Flopping Retinal in Microbial Rhodopsins as a Template for a Farnesyl/Prenyl Flip-Flop Model in Eukaryote GPCRs

Thirty years after the first description and modeling of G protein coupled receptors (GPCRs), information about their mode of action is still limited. One of the questions that is hard to answer is: how do the allosteric changes in the GPCR induced by, e.g., ligand binding in the end activate a G protein-dependent intracellular pathway (e.g., via the cAMP or the phosphatidylinositol signal pathways). Another question relates to the role of prenylation of G proteins. Today’s “consensus model” states that protein prenylation is required for the assembly of GPCR-G protein complexes. Although it is well-known that protein prenylation is the covalent addition of a farnesyl- or geranylgeranyl moiety to the C terminus of specific proteins, e.g., α or γ G protein, the reason for this strong covalent binding remains enigmatic. The arguments for a fundamental role for prenylation of G proteins other than just being a hydrophobic linker, are gradually accumulating. We uncovered a dilemma that at first glance may be considered physiologically irrelevant, however, it may cause a true change in paradigm. The consensus model suggests that the only functional role of prenylation is to link the G protein to the receptor. Does the isoprenoid nature of the prenyl group and its exact site of attachment somehow matter? Or, are there valid arguments favoring the alternative possibility that a key role of the G protein is to guide the covalently attached prenyl group to – and it hold it in – a very specific location in between specific helices of the receptor? Our model says that the farnesyl/prenyl group – aided by its covalent attachment to a G protein -might function in GPCRs as a horseshoe-shaped flexible (and perhaps flip-flopping) hydrophobic valve for restricting (though not fully inhibiting) the untimely passage of Ca2+, like retinal does for the passage of H+ in microbial rhodopsins that are ancestral to many GPCRs

Farnesol-Like Endogenous Sesquiterpenoids in Vertebrates: The Probable but Overlooked Functional ?Inbrome? Anti-Aging Counterpart of Juvenile Hormone of Insects?

Literature on the question whether the juvenile stage of vertebrates is hormonally regulated is scarce. It seems to be intuitively assumed that this stage of development is automated, and does not require any specific hormone(s). Such reasoning mimics the state of affairs in insects until it was shown that surgical removal of a tiny pair of glands in the head, the corpora allata, ended larval life and initiated metamorphosis. Decades later, the responsible hormone was found and named ?juvenile hormone? (JH) because when present, it makes a larva molt into another larval stage. JH is a simple ester of farnesol, a sesquiterpenoid present in all eukaryotes. Whereas vertebrates do not have an anatomical counterpart of the corpora allata, their tissues do contain farnesol-like sesquiterpenoids (FLS). Some display typical JH activity when tested in appropriate insect bioassays. Some FLS are intermediates in the biosynthetic pathway of cholesterol, a compound that insects and nematodes (=Ecdysozoa) cannot synthesize by themselves. They ingest it as a vitamin. Until a recent (2014) reexamination of the basic principle underlying insect metamorphosis, it had been completely overlooked that the Ca2+-pump (SERCA) blocker thapsigargin is a sesquiterpenoid that mimics the absence of JH in inducing apoptosis. In our opinion, being in the juvenile state is primarily controlled by endogenous FLS that participate in controlling the activity of Ca2+-ATPases in the sarco(endo)plasmic reticulum (SERCAs), not only in insects but in all eukaryotes. Understanding the control mechanisms of being in the juvenile state may boost research not only in developmental biology in general, but also in diseases that develop after the juvenile stage, e.g., Alzheimer?s disease. It may also help to better understand some of the causes of obesity, a syndrome that holometabolous last larval insects severely suffer from, and for which they found a very drastic but efficient solution, namely metamorphosis

Opioid prescribing in out-of-hours primary care in Flanders and the Netherlands:A retrospective cross-sectional study

BACKGROUND: Increased opioid prescribing has raised concern, as the benefits of pain relief not always outweigh the risks. Acute and chronic pain is often treated in a primary care out-of-hours (OOH) setting. This setting may be a driver of opioid use but the extent to which opioids are prescribed OOH is unknown. We aimed to investigate weak and strong opioid prescribing at OOH primary care services (PCS) in Flanders (Northern, Dutch-speaking part of Belgium) and the Netherlands between 2015 and 2019. METHODS: We performed a retrospective cross sectional study using data from routine electronic health records of OOH-PCSs in Flanders and the Netherlands (2015–2019). Our primary outcome was the opioid prescribing rate per 1000 OOH-contacts per year, in total and for strong (morphine, hydromorphone, oxycodone, oxycodone and naloxone, fentanyl, tapentadol, and buprenorphine and weak opioids (codeine combinations and tramadol and combinations) and type of opioids separately. RESULTS: Opioids were prescriped in approximately 2.5% of OOH-contacts in both Flanders and the Netherlands. In Flanders, OOH opioid prescribing went from 2.4% in 2015 to 2.1% in 2017 and then increased to 2.3% in 2019. In the Netherlands, opioid prescribing increased from 1.9% of OOH-contacts in 2015 to 2.4% in 2017 and slightly decreased thereafter to 2.1% of OOH-contacts. In 2019, in Flanders, strong opioids were prescribed in 8% of the OOH-contacts with an opioid prescription. In the Netherlands a strong opioid was prescribed in 57% of these OOH-contacts. Two thirds of strong opioids prescriptions in Flanders OOH were issued for patients over 75, in the Netherlands one third was prescribed to this age group. CONCLUSION: We observed large differences in strong opioid prescribing at OOH-PCSs between Flanders and the Netherlands that are likely to be caused by differences in accessibility of secondary care, and possibly existing opioid prescribing habits. Measures to ensure judicious and evidence-based opioid prescribing need to be tailored to the organisation of the healthcare system