Understanding the link between functional profiles and intelligence through dimensionality reduction and graph analysis.

There is a growing interest in neuroscience for how individual-specific structural and functional features of the cortex relate to cognitive traits. This work builds on previous research which, using classical high-dimensional approaches, has proven that the interindividual variability of functional connectivity profiles reflects differences in fluid intelligence. To provide an additional perspective into this relationship, the present study uses a recent framework for investigating cortical organization: functional gradients. This approach places local connectivity profiles within a common low-dimensional space whose axes are functionally interretable dimensions. Specifically, this study uses a data-driven approach focussing on areas where FC variability is highest across individuals to model different facets of intelligence. For one of these loci, in the right ventral-lateral prefrontal cortex (vlPFC), we describe an association between fluid intelligence and relative functional distance from sensory and high-cognition systems. Furthermore, the topological properties of this region indicate that with decreasing functional affinity with the latter, its functional connections are more evenly distributed across all networks. Participating in multiple functional networks may reflect a better ability to coordinate sensory and high-order cognitive systems.

A questionnaire to collect unintended effects of transcranial magnetic stimulation: A consensus based approach.

Transcranial magnetic stimulation (TMS) has been widely used in both clinical and research practice. However, TMS might induce unintended sensations and undesired effects as well as serious adverse effects. To date, no shared forms are available to report such unintended effects. This study aimed at developing a questionnaire enabling reporting of TMS unintended effects. A Delphi procedure was applied which allowed consensus among TMS experts. A steering committee nominated a number of experts to be involved in the Delphi procedure. Three rounds were conducted before reaching a consensus. Afterwards, the questionnaire was publicized on the International Federation of Clinical Neurophysiology website to collect further suggestions by the wider scientific community. A last Delphi round was then conducted to obtain consensus on the suggestions collected during the publicization and integrate them in the questionnaire. The procedure resulted in a questionnaire, that is the TMSens_Q, applicable in clinical and research settings. Routine use of the structured TMS questionnaire and standard reporting of unintended TMS effects will help to monitor the safety of TMS, particularly when applying new protocols. It will also improve the quality of data collection as well as the interpretation of experimental findings.

Striatal connectivity in pre-manifest Huntington's disease is differentially affected by disease burden.

BACKGROUND AND PURPOSE: Different amounts of cumulative exposure to the toxic mutant form of the huntingtin protein might underlie the distinctive pattern of striatal connectivity in pre-manifest Huntington's disease (pre-HD). The aim of this study was to investigate disease-burden-dependent cortical-striatal and subcortical-striatal loops at different pre-HD stages. METHODS: A total of 16 participants with pre-HD and 25 controls underwent magnetic resonance imaging to investigate striatal structural and functional connectivity (FC). Individuals with pre-HD were stratified into far-from-onset and close-to-onset disease groups according to the disease-burden score. Cortical-striatal and subcortical-striatal FC was investigated through seed-region of interest (ROI) and ROI-to-ROI approaches, respectively. The integrity of white-matter pathways originating from striatal seeds was investigated through probabilistic tractography. RESULTS: In far-from-onset pre-HD, the left caudate nucleus showed cortical increased FC in brain regions overlapping with the default mode network and increased coupling connectivity with the bilateral thalamus. By contrast, close-to-onset individuals showed increased fractional anisotropy (and mean diffusivity) in the right caudate nucleus and widespread striatal atrophy. Finally, we reported an association between cortical-caudate FC and caudate structural connectivity, although this did not survive multiple comparison correction. CONCLUSIONS: Functional reorganization of the caudate nucleus might underlie plasticity compensatory mechanisms that recede as individuals with pre-HD approach clinical symptom onset and neurodegeneration.

The cell type-specific signal proteins (pheromones) of protozoan ciliates.

In association with their mechanisms of self/non-self recognition (known as mating type systems), ciliates synthesize and constitutively secrete cell type-specific proteins into their extracellular medium. These proteins, designated as pheromones, have been isolated from species of Euplotes and shown to be members of families of structurally homologous molecules, all rich in intra-chain disulfide bonds and organized exclusively in helical conformation. Due to their similar architectures, they can interact with their membrane receptors in competition with one another and bind effectively to their cells of origin in autocrine fashion, or to other co-specific cells in paracrine fashion. In the former case, they promote the vegetative cell growth; in the latter, they induce cells to temporarily arrest their growth stage and shift to a mating (sexual) stage. These varied, context-dependent activities of ciliate pheromones imply an early evolution of basic properties of animal growth factors and cytokines in the unicellular eukaryotes.

The autocrine mitogenic loop of the ciliate Euplotes raikovi: the pheromone membrane-bound forms are the cell binding sites and potential signaling receptors of soluble pheromones.

Homologous proteins, denoted pheromones, promote cell mitotic proliferation and mating pair formation in the ciliate Euplotes raikovi, according to whether they bind to cells in an autocrine- or paracrine-like manner. The primary transcripts of the genes encoding these proteins undergo alternate splicing, which generates at least two distinct mRNAs. One is specific for the soluble pheromone, the other for a pheromone isoform that remains anchored to the cell surface as a type II protein, whose extracellular C-terminal region is structurally equivalent to the secreted form. The 15-kDa membrane-bound isoform of pheromone Er-1, denoted Er-1mem and synthesized by the same E. raikovi cells that secrete Er-1, has been purified from cell membranes by affinity chromatography prepared with matrix-bound Er-1, and its extracellular and cytoplasmic regions have been expressed as recombinant proteins. Using the purified material and these recombinant proteins, it has been shown that Er-1mem has the property of binding pheromones competitively through its extracellular pheromone-like domain and associating reversibly and specifically with a guanine nucleotide-binding protein through its intracellular domain. It has been concluded that the membrane-bound pheromone isoforms of E. raikovi represent the cell effective pheromone binding sites and are functionally equipped for transducing the signal generated by this binding.

Structure-function relationships of pheromones of the ciliate Euplotes raikovi with mammalian growth factors: cross-reactivity between Er-1 and interleukin-2 systems.

Diffusible protein signals of the ciliate Euplotes raikovi, denoted as pheromones, have functionally been linked with prototypic growth factors of animal cells by the demonstration that they not only induce a temporary cell union in mating pairs, by acting in a paracrine-like fashion, but can also bind to cells in autocrine fashion and promote their vegetative (mitotic) proliferation. It is now shown that pheromone Er-1 is capable of binding to the alpha and beta chains of the multimeric IL-2 receptor on mammalian cells and that IL-2 can, in turn, bind to the putative cell receptor of this pheromone. Similarities in the IL-2 and Er-1 structures support these findings and raise controversial implications with regard to their evolutionary significance.

Autocrine mitogenic activity of pheromones produced by the protozoan ciliate Euplotes raikovi.

Diffusible polypeptide pheromones (formerly referred to as mating-type factors, sex factors or gamones), which distinguish otherwise morphologically identical vegetative cell (mating) types from one another, are produced by some species of ciliates. Their most striking effect can be observed by exposing cells of one type to a pheromone secreted by another co-specific cell type. In the presence of this 'non-self' signal, these cells interrupt their vegetative life to unite temporarily in mating pairs. Thus ciliate pheromones have traditionally been associated only with mating induction. However, the identification of autocrine pheromone receptors suggests a broader role, which is supported by the hypothesis that ciliates evolved their mating-type mechanism for pursuing self-recognition. We now report studies, in the cosmopolitan marine sand-dwelling protozoan ciliate Euplotes raikovi, demonstrating that these molecules promote the vegetative reproduction (mitogenic proliferation or growth) of the same cells from which they originate. As, understandably, such autocrine pheromone activity is primary to that of targeting and inducing a foreign cell to mate (paracrine functions), this finding provides an example of how the original function of a molecule can be obscured during evolution by the acquisition of a new one.

Chemical signaling in ciliates.

For long, our knowledge of the biology of ciliate pheromones has long relied solely upon the study of the two structurally unrelated "gamones" identified in culture filtrates of a Blepharisma species. However, the characterization of a number of polypeptide pheromones secreted by Euplotes raikovi and E. octocarinatus has now established that structural relationships of homology usually link these molecules, which is consistent with the genetic basis of the mating type systems evolved by these species. In this context, our growing appreciation of the conserved and variable elements of the pheromone architecture should foster progress in the understanding of pheromone-receptor interactions and thus, provide important clues into pheromone mechanisms of action.

Primary structure of Euplotes raikovi pheromones: comparison of five sequences of pheromones from cells with variable mating interactions.

The amino acid sequences of five pheromones, Er-2, Er-3, Er-9, Er-11, and Er-20, secreted by cells of different mating types of the ciliated protozoa Euplotes raikovi, have been determined by automated Edman analyses of the whole proteins and germane fragments. In each case, the molecular mass was determined by plasma desorption or laser desorption mass spectrometry and was in excellent agreement with the calculated values. Where available, the determined sequences were also in accord with the corresponding segments of the precursor molecules predicted from relevant nucleic acid sequences. Of the five, two were found to be identical (Er-2 and Er-9) and one (Er-3) was identical to a pheromone previously sequenced (Er-1), even though mating pair formation was found to take place (although to a limited extent) when cells secreting those pheromones were combined in a mixture. Comparison of the five unique sequences suggested a closer relationship between Er-1 (Er-3) and Er-10 and between Er-11 and Er-20 (44% and 56% identity, respectively) than was generally observed among the other members. This pairing was also supported by hydrophobicity analyses. Interestingly, Er-20 cannot, as a rule, induce cell union in any of the other cell types, including cells secreting Er-11, despite the fact that Er-20 and Er-11 are the most similar of the five unique sequences. Thus sequence identity and secondary structure profiles are not a good indicator of biological relatedness as manifested in heterologous receptor interaction.

Developmental analysis of the cell recognition mechanism in the ciliate Euplotes raikovi.

Euplotes raikovi, like other ciliates, passes through a postconjugal immaturity, operatively identified by an apparent cell inability to form mating pairs under experimental conditions that are the same as those used for inducing mating at maturity. In cells homozygous for the gene mat-2, which controls the pheromone Er-2, Er-2 mRNA synthesis and mature Er-2 secretion were shown to start from the very beginning of the life cycle and continue throughout immaturity, although to extents estimated to be 5- to 10-fold lower than at maturity. In addition, experiments of 125I-Er-2 binding and crosslinking provided evidence that autocrine pheromone-binding sites, showing values of the dissociation constant of the order of 10(-9) M, are on the surface of immature cells. The number of these sites per cell was estimated to increase from less than 10(6) per cell of 5-7 fissions of age, to about 16 x 10(6) at maturity. These results were taken to suggest that a pheromone-receptor production is stimulated during immaturity by autocrine pheromone binding to cells and that this production might be essential for the development of a pheromone-receptor density high enough to transform the cell from "immature" to "adult," that is competent to respond as well to pheromones of conspecific, genetically different cells.

Specific and common epitopes in mating pheromones of Euplotes raikovi revealed by monoclonal antibodies.

Polypeptide mating pheromones Er-1 and Er-2, purified from the supernatant of Euplotes raikovi cultures of mating type I and mating type II, respectively, were used to immunize mice and obtain monoclonal antibodies. Five hybridoma clones producing antibodies specific to the mating pheromones were selected. They were analyzed for immunospecificity by immunoperoxidase assay, immunoblotting, and for their efficacy in inhibition of mating pheromone activity. Monoclonal antibodies from two hybridoma clones recognized only the mating pheromone used as antigen: those from the other three clones reacted, to comparable extents, with both mating pheromones. On the basis of these results it was assumed that two immunogenic sites exist in Er-1 and Er-2, one specific and the other common to both mating pheromones.