Transdiagnostic phenomena of psychopathology in the context of the RDoC: protocol of a multimodal cross-sectional study

In the past, affective and cognitive processes related to psychopathology have been examined within the boundaries of phenotype-based diagnostic labels, which has led to inconsistent findings regarding their underlying operating principles. Investigating these processes dimensionally in healthy individuals and by means of multiple modalities may provide additional insights into the psychological and neuronal mechanisms at their core. The transdiagnostic phenomena Neuroticism and Rumination are known to be closely linked. However, the exact nature of their relationship remains to be elucidated. The same applies to the associations between Hedonic Capacity, Negativity Bias and different Emotion Regulation strategies. This multimodal cross-sectional study examines the relationship of the transdiagnostic phenomena Neuroticism and Rumination as well as Hedonic Capacity, the Negativity Bias and Emotion Regulation from a RDoC (Research Domain Criteria) perspective. A total of 120 currently healthy subjects (past 12 months) will complete several questionnaires regarding personality, emotion regulation, hedonic capacity, and psychopathologies as well as functional magnetic resonance imaging (fMRI) during cognitive and emotional processing, to obtain data on the circuit, behavioral and self-report level. This study aims to contribute to the understanding of the relationship between cognitive and affective processes associated with psychopathologies as well as their neuronal correlates. Ultimately, a grounded understanding of these processes could guide improvement of diagnostic labels and treatments. Limitations include the cross-sectional design and the limited variability in psychopathology scores due to the restriction of the sample to currently healthy subjects

Functional activity and connectivity signatures of ketamine and lamotrigine during negative emotional processing: a double-blind randomized controlled fMRI study

Ketamine is a highly effective antidepressant (AD) that targets the glutamatergic system and exerts profound effects on brain circuits during negative emotional processing. Interestingly, the effects of ketamine on brain measures are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release. Examining the antagonistic effects of ketamine and lamotrigine on glutamate transmission holds promise to identify effects of ketamine that are mediated through changes in the glutamatergic system. Investigating this modulation in relation to both the acute and sustained effects of ketamine on functional activity and connectivity during negative emotional processing should therefore provide novel insights. 75 healthy subjects were investigated in a double-blind, single-dose, randomized, placebo-controlled, parallel-group study with three treatment conditions (ketamine, lamotrigine pre-treatment, placebo). Participants completed an emotional face viewing task during ketamine infusion and 24 h later. Acute ketamine administration decreased hippocampal and Default Mode Network (DMN) activity and increased fronto-limbic coupling during negative emotional processing. Furthermore, while lamotrigine abolished the ketamine-induced increase in functional connectivity, it had no acute effect on activity. Sustained (24 h later) effects of ketamine were only found for functional activity, with a significant reduction in the posterior DMN. This effect was blocked by pretreatment with lamotrigine. Our results suggest that both the acute increases in fronto-limbic coupling and the delayed decrease in posterior DMN activity, but not the attenuated limbic and DMN recruitment after ketamine, are mediated by altered glutamatergic transmission

Development of a Novel Virtual Screening Cascade Protocol to Identify Potential Trypanothione Reductase Inhibitors

The implementation of a novel sequential computational approach that can be used effectively for virtual screening and identification of prospective ligands that bind to trypanothione reductase (TryR) is reported. The multistep strategy combines a ligand-based virtual screening for building an enriched library of small molecules with a docking protocol (AutoDock, X-Score) for screening against the TryR target. Compounds were ranked by an exhaustive conformational consensus scoring approach that employs a rank-by-rank strategy by combining both scoring functions. Analysis of the predicted ligand-protein interactions highlights the role of bulky quaternary amine moieties for binding affinity. The scaffold hopping (SHOP) process derived from this computational approach allowed the identification of several chemotypes, not previously reported as antiprotozoal agents, which includes dibenzothiepine, dibenzooxathiepine, dibenzodithiepine, and polycyclic cationic structures like thiaazatetracyclo-nonadeca-hexaen-3-ium. Assays measuring the inhibiting effect of these compounds on T. cruzi and T. brucei TryR confirm their potential for further rational optimization

An Endogenous Foamy-like Viral Element in the Coelacanth Genome

Little is known about the origin and long-term evolutionary mode of retroviruses. Retroviruses can integrate into their hosts' genomes, providing a molecular fossil record for studying their deep history. Here we report the discovery of an endogenous foamy virus-like element, which we designate ‘coelacanth endogenous foamy-like virus’ (CoeEFV), within the genome of the coelacanth (Latimeria chalumnae). Phylogenetic analyses place CoeEFV basal to all known foamy viruses, strongly suggesting an ancient ocean origin of this major retroviral lineage, which had previously been known to infect only land mammals. The discovery of CoeEFV reveals the presence of foamy-like viruses in species outside the Mammalia. We show that foamy-like viruses have likely codiverged with their vertebrate hosts for more than 407 million years and underwent an evolutionary transition from water to land with their vertebrate hosts. These findings suggest an ancient marine origin of retroviruses and have important implications in understanding foamy virus biology

How Protein Stability and New Functions Trade Off

Numerous studies have noted that the evolution of new enzymatic specificities is accompanied by loss of the protein's thermodynamic stability (ΔΔG), thus suggesting a tradeoff between the acquisition of new enzymatic functions and stability. However, since most mutations are destabilizing (ΔΔG>0), one should ask how destabilizing mutations that confer new or altered enzymatic functions relative to all other mutations are. We applied ΔΔG computations by FoldX to analyze the effects of 548 mutations that arose from the directed evolution of 22 different enzymes. The stability effects, location, and type of function-altering mutations were compared to ΔΔG changes arising from all possible point mutations in the same enzymes. We found that mutations that modulate enzymatic functions are mostly destabilizing (average ΔΔG = +0.9 kcal/mol), and are almost as destabilizing as the “average” mutation in these enzymes (+1.3 kcal/mol). Although their stability effects are not as dramatic as in key catalytic residues, mutations that modify the substrate binding pockets, and thus mediate new enzymatic specificities, place a larger stability burden than surface mutations that underline neutral, non-adaptive evolutionary changes. How are the destabilizing effects of functional mutations balanced to enable adaptation? Our analysis also indicated that many mutations that appear in directed evolution variants with no obvious role in the new function exert stabilizing effects that may compensate for the destabilizing effects of the crucial function-altering mutations. Thus, the evolution of new enzymatic activities, both in nature and in the laboratory, is dependent on the compensatory, stabilizing effect of apparently “silent” mutations in regions of the protein that are irrelevant to its function

The Contrasting Effect of Macromolecular Crowding on Amyloid Fibril Formation

Amyloid fibrils associated with neurodegenerative diseases can be considered biologically relevant failures of cellular quality control mechanisms. It is known that in vivo human Tau protein, human prion protein, and human copper, zinc superoxide dismutase (SOD1) have the tendency to form fibril deposits in a variety of tissues and they are associated with different neurodegenerative diseases, while rabbit prion protein and hen egg white lysozyme do not readily form fibrils and are unlikely to cause neurodegenerative diseases. In this study, we have investigated the contrasting effect of macromolecular crowding on fibril formation of different proteins.As revealed by assays based on thioflavin T binding and turbidity, human Tau fragments, when phosphorylated by glycogen synthase kinase-3β, do not form filaments in the absence of a crowding agent but do form fibrils in the presence of a crowding agent, and the presence of a strong crowding agent dramatically promotes amyloid fibril formation of human prion protein and its two pathogenic mutants E196K and D178N. Such an enhancing effect of macromolecular crowding on fibril formation is also observed for a pathological human SOD1 mutant A4V. On the other hand, rabbit prion protein and hen lysozyme do not form amyloid fibrils when a crowding agent at 300 g/l is used but do form fibrils in the absence of a crowding agent. Furthermore, aggregation of these two proteins is remarkably inhibited by Ficoll 70 and dextran 70 at 200 g/l.We suggest that proteins associated with neurodegenerative diseases are more likely to form amyloid fibrils under crowded conditions than in dilute solutions. By contrast, some of the proteins that are not neurodegenerative disease-associated are unlikely to misfold in crowded physiological environments. A possible explanation for the contrasting effect of macromolecular crowding on these two sets of proteins (amyloidogenic proteins and non-amyloidogenic proteins) has been proposed

Frequent and Recent Human Acquisition of Simian Foamy Viruses Through Apes' Bites in Central Africa

Human infection by simian foamy viruses (SFV) can be acquired by persons occupationally exposed to non-human primates (NHP) or in natural settings. This study aimed at getting better knowledge on SFV transmission dynamics, risk factors for such a zoonotic infection and, searching for intra-familial dissemination and the level of peripheral blood (pro)viral loads in infected individuals. We studied 1,321 people from the general adult population (mean age 49 yrs, 640 women and 681 men) and 198 individuals, mostly men, all of whom had encountered a NHP with a resulting bite or scratch. All of these, either Pygmies (436) or Bantus (1085) live in villages in South Cameroon. A specific SFV Western blot was used and two nested PCRs (polymerase, and LTR) were done on all the positive/borderline samples by serology. In the general population, 2/1,321 (0.2%) persons were found to be infected. In the second group, 37/198 (18.6%) persons were SFV positive. They were mostly infected by apes (37/39) FV (mainly gorilla). Infection by monkey FV was less frequent (2/39). The viral origin of the amplified sequences matched with the history reported by the hunters, most of which (83%) are aged 20 to 40 years and acquired the infection during the last twenty years. The (pro)viral load in 33 individuals infected by a gorilla FV was quite low (<1 to 145 copies per 105 cells) in the peripheral blood leucocytes. Of the 30 wives and 12 children from families of FV infected persons, only one woman was seropositive in WB without subsequent viral DNA amplification. We demonstrate a high level of recent transmission of SFVs to humans in natural settings specifically following severe gorilla bites during hunting activities. The virus was found to persist over several years, with low SFV loads in infected persons. Secondary transmission remains an open question