IL-23R and TCR signaling drives the generation of neonatal Vgamma9Vdelta2 T cells expressing high levels of cytotoxic mediators and producing IFN-gamma and IL-17

The immune system in early life is regarded as immature. However, the IL-12 family member IL-23 is highly produced upon TLR stimulation by neonatal DCs. Human adult Vγ9Vδ2 T cells can be stimulated specifically via their TCR by phosphoantigens (as the pathogen-derived HMB-PP) or agents and infections that lead to their endogenous accumulation (as the aminobisphosphonate zoledronate). As increasing evidence indicates that γδ T cells are especially important in early life, we investigated the effect of IL-23 on neonatal Vγ9Vδ2 T cells stimulated via their TCR. Zoledronate induced clear proliferation and IFN-γ production in neonatal Vγ9Vδ2 T cells. In contrast, HMB-PP did not elicit a distinct response unless at high concentrations. Addition of IL-23 to zoledronate enhanced the expression of IFN-γ and generated a distinct, IFN-γ-negative, neonatal Vγ9Vδ2 T cell population producing IL-17. Furthermore, IL-23 significantly enhanced the expression of a range of cytotoxic mediators (perforin, granzymes, granulysin). Although the costimulatory effect of IL-23 on IFN-γ and cytotoxic mediators was also observed within adult Vγ9Vδ2 T cells, the induction of an IL-17+IFN-γ- subset was unique to neonatal Vγ9Vδ2 T cells. In conclusion, neonatal DC-derived IL-23 combined with specific TCR signaling drives the generation of neonatal Vγ9Vδ2 T cells equipped with a range of cytotoxic mediators and distinct subpopulations producing IFN-γ and IL-17.     

Computational chemical biology: identification of small molecular probes that discriminate between members of target protein families

Research in chemical biology focuses on the use of small molecules to study protein functions and distinguish between different targets and their functional properties. In this context, it would be helpful to better understand which currently available active compounds have a potential to differentiate between different targets belonging to a protein family. Such compounds might be utilized as a starting point for the development of small molecular probes that distinguish one or more targets from others within a family of interest. To address this question, we have designed a computational approach for data mining that involves the generation and quantitative assessment of selectivity profiles for compounds active against a protein family. Selectivity profiles were generated and represented in a consistent manner, and an intuitive weighting scheme was applied to account for the target differentiation potential of individual compounds. Based on a thorough analysis of public domain compound data, we have prioritized currently available active small molecules that displayed a tendency to differentiate between targets belonging to 15 different families. We have been particularly interested in identifying compounds having the highest general target differentiation potential within a family (rather than identifying compounds that are selective for one target over one or more others). These compounds might be utilized in target profiling and as starting points for further chemical exploration and probe generation. A compendium of prioritized active compounds with informative selectivity profiles is provided.     

Expression of chloride intracellular channel protein 1 (CLIC1) and tumor protein D52 (TPD52) as potential biomarkers for colorectal cancer

ObjectivesUnequivocal biomarkers are needed to predict susceptibility and progression of colorectal cancer.Design and methodsPaired samples of tumor and normal tissue from six patients with colorectal cancer of different localization, pTNM stage and grade were employed in the present study. MS analysis was used to identify differentially regulated proteins after 2-DE separation and densitometric analysis.ResultsDensitometric analysis revealed differential abundance of 55 spots in tumor as compared to normal tissues. Thirty nine out of 55 spots were unambiguously identified by MS representing 32 different proteins. CLIC1, TPD52 and FABPL were consistently overexpressed (> 3-fold, P < 0.05) in all tumor tissue samples, while TPM1, TPM2, TPM3, TAGL and MLRN were consistently down-regulated (> 3-fold, P < 0.05) compared to normal tissue.ConclusionsCLIC1 and TPD52 were significantly (P < 0.05) up-regulated in all cases of colorectal cancer investigated, irrespective of localization, pTNM stage and grade of colon cancer highlighting their potential to serve as new biomarkers.     

Identification of Orthologous Target Pairs with Shared Active Compounds and Comparison of Organism‐specific Activity Patterns

A systematic search for active small molecules shared by orthologous targets was carried out, leading to the identification of 803 compound‐based orthologous target pairs covering a total of 938 orthologues, 358 unique targets and 98 organisms. Many orthologous target pairs were found to have substantial compound coverage, enabling the introduction of an orthologous target pairs classification including ‘organism cliffs’ and ‘potency‐retaining’ pairs. A total of 158 orthologous target pairs involving human orthologues were identified, which were typically associated with drug discovery‐relevant targets, organism combinations and compound data. Orthologous target pairs with human orthologues included 83 potency‐retaining orthologous target pairs covering a variety of targets and organisms. On the basis of these orthologous target pairs, the compound search was further extended and 1149 potent compounds were identified that only had reported activities for non‐human orthologues of 48 therapeutic targets, but not their human counterparts, hence providing a large pool of candidate compounds for further evaluation. The complete set of orthologous target pairs identified in our analysis, the orthologous target pairs classification including associated data and all candidate compounds are made freely available.     

Anticipated action consequences as a nexus between action and perception: evidence from event-related potentials

We used high-density event-related potentials (ERP) in a modified flanker paradigm to study the role of anticipated action consequences in action planning and the role of anticipation in the perception of action consequences. Prior to the experiment, participants were trained to classify target letters in a four-alternative forced-choice task; another letter was presented as an effect following each response. After participants had thus acquired the response-effect contingencies, in the experiment effect letters were presented as flankers to target letters. Effect-compatible flankers were letters that were learned as effects of the correct response to the target; effect-incompatible ones were learned as effects of other responses; neutral flankers were never presented as action effects. To help distinguish early and late effects of flankers on target processing, flankers were presented either simultaneously with the target or after a delay. We found that effect-incompatible flankers resulted in longer, than other flankers, time between the onset of the response-locked lateralized readiness potential and the response, indicating extended motor processing. ERP evoked by the effect-incompatible flankers differed from those evoked by other flankers in early perceptual component P1 and in later frontal component P2 reflecting stimulus evaluation and conflict detection. These results show that anticipating action consequences involves brain systems ranging from perceptual to executive; anticipated action effects constitute a link between perception and action.     

Der Einfluß der mechanischen Faktoren auf die Struktur der Zwischenwirbelscheiben

Zusammenfassung An 70 weißen Mäusen wurden die vorderen Extremitäten amputiert und die Wirbelsäule 3, 6 und 12 Monate nach der Operation untersucht. Dabei wurde die Bildung terminaler knöcherner Scheiben an dem Wirbelkörper sowie Desorganisation des Epiphysenknorpels festgestellt. In den hyalinen Knorpelscheiben treten Verknöcherungsherde auf; der fibröse Ring verdünnt sich und grenzt sich vom hyalinen Knorpel scharf ab. Es wird die Bedeutung der mechanischen Faktoren für das Auftreten der strukturellen Veränderungen diskutiert.

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Summary The spines of 70 white mice, subjected to forelimb amputation, were investigated 3, 6 and 12 months after bipedalization. Formation was established of terminal bone plates of the vertebral bodies as well as disorganization of the epiphyseal cartilage. The appearance of cavities is observed within the hyalin cartilage plates, filled up with blood cells, whilst the annulus fibrosus becomes thinner and displays clearcut separation from the hyalin cartilage. The role played by mechanical factors for the occurrence of structural changes is discussed.

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Résumé Les colonnes vertébrales de 70 souris blanches on été examinées le 3-ème, le 6-ème et le 12-ème mois après amputation des membres antérieures. On a observé la formation de lamelles osseuses terminales dans les corps vertébraux et une desorganisation des cartilages epiphisères. Dans les lamelles du cartilage hyalin ont été constatées des cavités remplies de cellules sanguines. L'anneau fibreus est aminci et ses lamelles périphériques se distinguent bien du cartilage hyalin. Le rôle des facteurs méchaniques à l'égard des changements structurels est discuté.