Protective effect of a germline, IL-17-neutralizing antibody in murine models of autoimmune inflammatory disease.

Monoclonal antibodies (mAbs) inhibiting cytokines have recently emerged as new drug modalities for the treatment of chronic inflammatory diseases. Interleukin-17 (IL-17) is a T-cell-derived central mediator of autoimmunity. Immunization with Qβ-IL-17, a virus-like particle based vaccine, has been shown to produce autoantibodies in mice and was effective in ameliorating disease symptoms in animal models of autoimmunity. To characterize autoantibodies induced by vaccination at the molecular level, we generated mouse mAbs specific for IL-17 and compared them to germline Ig sequences. The variable regions of a selected hypermutated high-affinity anti-IL-17 antibody differed in only three amino acid residues compared to the likely germline progenitor. An antibody, which was backmutated to germline, maintained a surprisingly high affinity (0.5 nM). The ability of the parental hypermutated antibody and the derived germline antibody to block inflammation was subsequently tested in murine models of multiple sclerosis (experimental autoimmune encephalomyelitis), arthritis (collagen-induced arthritis), and psoriasis (imiquimod-induced skin inflammation). Both antibodies were able to delay disease onset and significantly reduced disease severity. Thus, the mouse genome unexpectedly encodes for antibodies with the ability to functionally neutralize IL-17 in vivo.

Non-canonical actions of Nogo-A and its receptors

Nogo-A is a myelin associated protein and one of the most potent neurite growth inhibitors in the central nervous system. Interference with Nogo-A signaling has thus been investigated as therapeutic target to promote functional recovery in CNS injuries. Still, the finding that Nogo-A presents a fairly ubiquitous expression in many types of neurons in different brain regions, in the eye and even in the inner ear suggests for further functions besides the neurite growth repression. Indeed, a growing number of studies identified a variety of functions including regulation of neuronal stem cells, modulation of microglial activity, inhibition of angiogenesis and interference with memory formation. Aim of the present commentary is to draw attention on these less well-known and sometimes controversial roles of Nogo-A. Furthermore, we are addressing the role of Nogo-A in neuropathological conditions such as ischemic stroke, schizophrenia and neurodegenerative diseases.

Theoretical models of planetary system formation II. Post-formation evolution

Aims. We extend the results of planetary formation synthesis by computing the long-term evolution of synthetic systems from the clearing of the gas disk into the dynamical evolution phase. Methods. We use the symplectic integrator SyMBA to numerically integrate the orbits of planets for 100 Myr, using populations from previous studies as initial conditions. Results. We show that within the populations studied, mass and semimajor axis distributions experience only minor changes from post-formation evolution. We also show that, depending upon their initial distribution, planetary eccentricities can statistically increase or decrease as a result of gravitational interactions. We find that planetary masses and orbital spacings provided by planet formation models do not result in eccentricity distributions comparable to observed exoplanet eccentricities, requiring other phenomena, such as stellar fly-bys, to account for observed eccentricities.

Global models of planet formation and evolution

Despite the strong increase in observational data on extrasolar planets, the processes that led to the formation of these planets are still not well understood. However, thanks to the high number of extrasolar planets that have been discovered, it is now possible to look at the planets as a population that puts statistical constraints on theoretical formation models. A method that uses these constraints is planetary population synthesis where synthetic planetary populations are generated and compared to the actual population. The key element of the population synthesis method is a global model of planet formation and evolution. These models directly predict observable planetary properties based on properties of the natal protoplanetary disc, linking two important classes of astrophysical objects. To do so, global models build on the simplified results of many specialized models that address one specific physical mechanism. We thoroughly review the physics of the sub-models included in global formation models. The sub-models can be classified as models describing the protoplanetary disc (of gas and solids), those that describe one (proto)planet (its solid core, gaseous envelope and atmosphere), and finally those that describe the interactions (orbital migration and N-body interaction). We compare the approaches taken in different global models, discuss the links between specialized and global models, and identify physical processes that require improved descriptions in future work. We then shortly address important results of planetary population synthesis like the planetary mass function or the mass-radius relationship. With these statistical results, the global effects of physical mechanisms occurring during planet formation and evolution become apparent, and specialized models describing them can be put to the observational test. Owing to their nature as meta models, global models depend on the results of specialized models, and therefore on the development of the field of planet formation theory as a whole. Because there are important uncertainties in this theory, it is likely that the global models will in future undergo significant modifications. Despite these limitations, global models can already now yield many testable predictions. With future global models addressing the geophysical characteristics of the synthetic planets, it should eventually become possible to make predictions about the habitability of planets based on their formation and evolution.

Code-switching: a touchstone of models of bilingual language production

The goal of the present thesis was to investigate the production of code-switched utterances in bilinguals’ speech production. This study investigates the availability of grammatical-category information during bilingual language processing. The specific aim is to examine the processes involved in the production of Persian-English bilingual compound verbs (BCVs). A bilingual compound verb is formed when the nominal constituent of a compound verb is replaced by an item from the other language. In the present cases of BCVs the nominal constituents are replaced by a verb from the other language. The main question addressed is how a lexical element corresponding to a verb node can be placed in a slot that corresponds to a noun lemma. This study also investigates how the production of BCVs might be captured within a model of BCVs and how such a model may be integrated within incremental network models of speech production. In the present study, both naturalistic and experimental data were used to investigate the processes involved in the production of BCVs. In the first part of the present study, I collected 2298 minutes of a popular Iranian TV program and found 962 code-switched utterances. In 83 (8%) of the switched cases, insertions occurred within the Persian compound verb structure, hence, resulting in BCVs. As to the second part of my work, a picture-word interference experiment was conducted. This study addressed whether in the case of the production of Persian-English BCVs, English verbs compete with the corresponding Persian compound verbs as a whole, or whether English verbs compete with the nominal constituents of Persian compound verbs only. Persian-English bilinguals named pictures depicting actions in 4 conditions in Persian (L1). In condition 1, participants named pictures of action using the whole Persian compound verb in the context of its English equivalent distractor verb. In condition 2, only the nominal constituent was produced in the presence of the light verb of the target Persian compound verb and in the context of a semantically closely related English distractor verb. In condition 3, the whole Persian compound verb was produced in the context of a semantically unrelated English distractor verb. In condition 4, only the nominal constituent was produced in the presence of the light verb of the target Persian compound verb and in the context of a semantically unrelated English distractor verb. The main effect of linguistic unit was significant by participants and items. Naming latencies were longer in the nominal linguistic unit compared to the compound verb (CV) linguistic unit. That is, participants were slower to produce the nominal constituent of compound verbs in the context of a semantically closely related English distractor verb compared to producing the whole compound verbs in the context of a semantically closely related English distractor verb. The three-way interaction between version of the experiment (CV and nominal versions), linguistic unit (nominal and CV linguistic units), and relation (semantically related and unrelated distractor words) was significant by participants. In both versions, naming latencies were longer in the semantically related nominal linguistic unit compared to the response latencies in the semantically related CV linguistic unit. In both versions, naming latencies were longer in the semantically related nominal linguistic unit compared to response latencies in the semantically unrelated nominal linguistic unit. Both the analysis of the naturalistic data and the results of the experiment revealed that in the case of the production of the nominal constituent of BCVs, a verb from the other language may compete with a noun from the base language, suggesting that grammatical category does not necessarily provide a constraint on lexical access during the production of the nominal constituent of BCVs. There was a minimal context in condition 2 (the nominal linguistic unit) in which the nominal constituent was produced in the presence of its corresponding light verb. The results suggest that generating words within a context may not guarantee that the effect of grammatical class becomes available. A model is proposed in order to characterize the processes involved in the production of BCVs. Implications for models of bilingual language production are discussed.