New rock magnetic and paleomagnetic results for the 1.64 Ga Suomenniemi dyke swarm, SE Finland

Peer reviewe

Stochastic dynamics of virus capsid formation: direct versus hierarchical self-assembly

Background: In order to replicate within their cellular host, many viruses have developed self-assembly strategies for their capsids which are sufficiently robust as to be reconstituted in vitro. Mathematical models for virus self-assembly usually assume that the bonds leading to cluster formation have constant reactivity over the time course of assembly (direct assembly). In some cases, however, binding sites between the capsomers have been reported to be activated during the self-assembly process (hierarchical assembly). Results: In order to study possible advantages of such hierarchical schemes for icosahedral virus capsid assembly, we use Brownian dynamics simulations of a patchy particle model that allows us to switch binding sites on and off during assembly. For T1 viruses, we implement a hierarchical assembly scheme where inter-capsomer bonds become active only if a complete pentamer has been assembled. We find direct assembly to be favorable for reversible bonds allowing for repeated structural reorganizations, while hierarchical assembly is favorable for strong bonds with small dissociation rate, as this situation is less prone to kinetic trapping. However, at the same time it is more vulnerable to monomer starvation during the final phase. Increasing the number of initial monomers does have only a weak effect on these general features. The differences between the two assembly schemes become more pronounced for more complex virus geometries, as shown here for T3 viruses, which assemble through homogeneous pentamers and heterogeneous hexamers in the hierarchical scheme. In order to complement the simulations for this more complicated case, we introduce a master equation approach that agrees well with the simulation results. Conclusions: Our analysis shows for which molecular parameters hierarchical assembly schemes can outperform direct ones and suggests that viruses with high bond stability might prefer hierarchical assembly schemes. These insights increase our physical understanding of an essential biological process, with many interesting potential applications in medicine and materials science

The role of endosomal Toll-like receptors in the tumor microenvironment

Tumore bestehen aus malignen Zellen und dem Tumorstroma. Letzteres setzt sich aus nicht-hämatopoetischen Zellen und dem Immunzellinfiltrat zusammen und macht häufig einen Großteil der Tumormasse aus. Wechselwirkungen zwischen den Tumorzellen und dem Stroma beeinflussen die Biologie der beteiligten Zellen und die Pathophysiologie der Erkrankung. Toll-like Rezeptoren (TLRs) haben eine Schlüsselfunktion in der Aktivierung des Immunsystems. Die Aktivierung von TLRs kann anti-tumorale Effekte induzieren, die vor allem durch den Einsatz therapeutischer exogener Liganden hervorgerufen werden, während eine pro-tumorale Wirkung vorrangig für endogene Liganden beschrieben wurde. Um diese gegensätzlichen Befunde besser verstehen zu können, wurden in dieser Arbeit die Rolle endosomaler TLRs auf den verschiedenen Kompartimenten der Tumormikroumgebung analysiert. Initiale Untersuchungen der vorliegenden Arbeit sollten in TLR3/7/9-/- Mäusen Aufschluss darüber geben, welche TLRs und nachfolgende Signalwege an der Tumorabstoßung beteiligt sind. Die Untersuchung von Einzel- und Doppel-TLR-Knockoutmäusen zeigte, dass nur durch das Fehlen aller drei endosomaler Rezeptoren eine effiziente Abstoßung eintrat. Die Beteiligung mehrere TLR-Signalwege wurde durch die Tumorabstoßung in den MyD88/Trif-/- Mäusen bestätigt. Interessanterweise entwickelten jedoch die meisten der TLR2/3/4/7/9-Knockoutmäuse einen soliden Tumor, was für einen entgegengesetzten Effekt der endosomalen TLRs (3, 7, 9) und der Oberflächenrezeptoren TLR2 und TLR4 spricht. Um den relativen Beitrag des nicht-hämatopoetischen Stromas und des Immunzellinfiltrats an der Tumorregression zu untersuchen, wurden Knochenmarkchimären eingesetzt. Deren Untersuchung zeigte, dass beide Kompartimente an der Abstoßungsreaktion beteiligt waren. Dies wurde durch den adoptiven Transfer markierter Milzzellen bestätigt, da es nur zur Immunzellrekrutierung in den Tumor kam, wenn auf beiden Kompartimenten endosomale TLRs fehlten. Anschließende Untersuchungen des nicht-hämatopoetischen Stromas zeigten deutliche Unterschiede in der Ausbildung von Tumorgefäßen. Während die Tumore der WT Mäuse von einem feinen Kapillarsystem durchzogen wurden, bildeten sich in den Tumoren der TLR3/7/9-/- Mäuse eine geringere Anzahl heterogener Gefäße, die einen deutlich größeren Durchmesser aufwiesen, von Perizyten ummantelt waren und nicht alle Bereiche des Tumors versorgten. Im Kompartiment des hämatopoetischen Stromas konnte gezeigt werden, dass eine lokale anti-tumorale Immunreaktion für die Tumorabstoßung verantwortlich war. Während systemisch keine Unterschiede in der Aktivierung von dendritischen Zellen und T-Zellen festgestellt werden konnten, waren die Tumore der TLR3/7/9-/- Mäuse sehr stark mit Zellen des angeborenen und des adaptiven Immunsystems infiltriert. Durch Depletionsversuche konnte demonstriert werden, dass sowohl CD4+ als auch CD8+ T-Zellen für die Abstoßung verantwortlich waren. Dies wurde durch den Befund bestätigt, dass TLR3/7/9-/- Mäuse nach einmaliger Injektion der Tumorzellen eine Immunität gegen diese Zellen ausbildeten, sodass es zu keiner erneuten Ausbildung eines Tumors kommen konnte. Zusammenfassend konnte in der vorliegenden Arbeit zum ersten Mal gezeigt werden, dass durch das Fehlen der endosomalen Toll-like Rezeptoren TLR3, TLR7 und TLR9 Veränderungen in der Tumormikroumgebung auftreten, die zu eine T-Zell-abhängigen Tumorabstoßung führten. Daraus lässt sich ein pro-tumoraler Effekt dieser Rezeptoren in der WT-Situation bzw. die Ermöglichung einer anti-tumoralen Immunreaktion in den TLR3/7/9-/- Mäusen ableiten. Dieser Befund ist von besonderer Bedeutung, da endosomale TLRs bislang vorwiegend mit exogener therapeutischer Stimulation in Verbindung gebracht wurden und die Stimulation durch endogene Liganden kaum untersucht ist. In dieser Arbeit konnte nun gezeigt werden, dass, unabhängig von therapeutischer Intervention, die endosomale TLR-Expression auf den hämatopoetischen und nicht-hämatopoetischen Zellen das Tumorwachstum beeinflussen kann. Die TLR-Aktivierung durch bislang nicht identifizierte endogene Liganden könnte zu einer pro-tumoralen Stimulation der Tumorzellen führen. Daher könnte die Inhibierung endosomaler TLRs eine neue Möglichkeit der therapeutischen Intervention bei bestimmten Tumorerkrankungen darstellen.Tumors consist of malignant cells and the tumor stroma, which is composed of non-hematopoietic cells and the infiltrating immune cells. Often the stroma represents the major fraction of the whole tumor mass. The interaction between tumor and stromal cells influences the biology of the involved cells and the pathophysiology of the disease. Toll-like receptors (TLRs) are known as key players in immune activation. The activation of TLRs can induce anti-tumor effects, which are mostly generated by the use of therapeutic exogenous ligands, while pro-tumor effects are primarily described for endogenous ligands. To better understand these contrary indications, the impact of endosomal TLR expression on different compartments of the tumor microenvironment was analyzed in this thesis. Firstly the aim was to investigate which TLRs and subsequent pathways are involved in the tumor regression in the TLR3/7/9-/- mice. Tumor growth analysis in single and double TLR knockout mice showed that depletion of all three TLRs is necessary to induce tumor rejection. The involvement of several TLR pathways was confirmed by tumor rejection in MyD88/Trif-/- mice. Surprisingly, the majority of TLR2/3/4/7/9-/- mice developed a solid tumor, revealing a converse function of endosomal TLRs (3, 7, 9) and TLR2/4 located on the cell surface. To identify the relative contribution of the non-hematopoietic stromal cells and the infiltrating immune cells to tumor regression, bone marrow chimeras were generated. The investigation of these chimeras demonstrated the involvement of both compartments in the process of tumor rejection. This was confirmed by the adaptive transfer of labeled splenocytes and it was found that only if both compartments were deficient for endosomal TLRs then immune cells would be recruited to the tumor. Further investigation of the non-hematopoietic compartment revealed clear differences in the blood vessel development. While in WT mice, tumors were supplied by a fine capillary network, TLR3/7/9-/- mice developed a reduced number of tumor vessels which were characterized by a heterogeneous structure. TLR-deficient vessels showed an increased diameter and coverage by pericytes compared to tumor vessels of WT mice. Investigation of the hematopoietic compartment indicates a local anti-tumor response of the immune system. While no systemic activation of dendritic cells or T cells could be determined, tumors of TLR mice were highly infiltrated by innate and adaptive immune cells. Depletion of CD4+ or CD8+ T cells in vivo demonstrated that both cell types are necessary for tumor rejection. This was verified by the observation, that TLR3/7/9-/- tumor regressor mice were protected against a secondary challenge by the same tumor cell line. In summary, the experiments of this thesis showed for the first time that depletion of endosomal TLR3, TLR7 and TLR9 induces modification of the tumor microenvironment resulting in a T cell dependent tumor rejection. The data suggest a tumor promoting effect in the WT situation or alternatively the enabling of previously inactive anti-tumor mechanisms in TLR3/7/9-/- mice. These findings are of relevance as previously endosomal TLRs were mainly associated with exogenous therapeutic TLR stimulation while the relevance of endogenous signaling via these TLRs is largely unknown. This study now shows an effect of endosomal TLR expression by non-hematopoietic and hematopoietic stroma cells on tumor growth in the absence of therapeutic intervention. TLR activation, by still elusive ligands, in different compartments of the tumor/stroma entity by endogenous ligands could promote tumor growth. Thus inhibition of endosomal TLRs could lead to new therapeutic options in solid tumors

Mesoproterozoic geomagnetic reversal asymmetry in light of new paleomagnetic and geochronological data for the Häme dyke swarm, Finland : Implications for the Nuna supercontinent

Baltica represents one of the key continents of the Mesoproterozoic supercontinent Nuna forming the core of it together with Laurentia and Siberia. This study presents new geochronological and paleomagnetic data obtained for Häme diabase dyke swarm in southern Finland. New U-Pb (baddeleyite) ages 1642 ± 2 Ma and 1647 ± 14 Ma for two reversely magnetized dykes are acquired. Demagnetization revealed a dual polarity remanent magnetization direction carried by magnetite. The combined normal (N) and reversed (R) polarity direction for 11 dykes (=sites) is D = 355.6°, I = -09.1° (k = 8.6 and α95 = 16.6°) yielding a paleomagnetic pole at 23.6°N, 209.8°E (K = 10.6 and A95 = 14.7°) with Van der Voo value Q = 7. N and R magnetized units for the Häme dyke swarm show asymmetry in declination values, probably caused by an age difference between the dykes. The Geocentric Axial Dipole (GAD) model indicates that all geomagnetic reversals should be symmetric (in inclination), yet it has been noted that this is not always the case (e.g. 1.57 Ga Satakunta and Åland dykes in Baltica). By analyzing global dual polarity paleomagnetic data we show that the GAD model is a valid assumption at 1.7 – 1.4 Ga and that the asymmetry between some normal and reversed polarities in global dual-polarity data sets appears randomly over time, and does not follow a global trend. Further, we show that in the case of Åland and Satakunta dykes an unremoved secondary magnetization component could explain the obtained asymmetry. GAD assumption is used to reconstruct the core of Nuna on equatorial latitudes using new data for Häme dykes. Paleomagnetic evidence suggest that maximum assembly of Nuna occurred at 1.5 Ga and the dispersal of the core is proposed to be associated with coeval 1.38 – 1.27 Ga magmatism in its core continents.Peer reviewe

The long shadow of early-change patterns: a 3-year follow-up after the use of a web-based intervention for mild to moderate depressive symptoms

Web-based interventions can be effective in treating depressivesymptoms. Patients with risk not responding to treatment havebeen identified by early change patterns. This study aims to examinewhether early changes are superior to baseline parameters in pre-dicting long-term outcome. In a randomized clinical trial with 409individuals experiencing mild to moderate depressive symptomsusing the web-based intervention deprexis, three latent classeswere identified (early response after registration, early responseafter screening and early deterioration) based on early change inthe first four weeks of the intervention. Baseline variables and theseclasses were included in a Stepwise Cox Proportional Hazard MultipleRegression to identify predictors associated with the onset of remis-sion over 36-months. Early change class was a significant predictor ofremission over 36 months. Compared to early deterioration afterscreening, both early response after registration and after screeningwere associated with a higher likelihood of remission. In sensitivityand secondary analyses, only change class consistently emerged asa predictor of long-term outcome. Early improvement in depressionsymptoms predicted long-term outcome and those showing earlyimprovement had a higher likelihood of long-term remission. Thesefindings suggest that early changes might be a robust predictor forlong-term outcome beyond baseline parameters

Pro- and antisaccades in children elicited by visual and acoustic targets - does modality matter?

Peer reviewedPublisher PD

Color Change Effect in an Organic-Inorganic Hybrid Material Based on a Porphyrin Diacid

Porphyrinic materials show a range of interesting and useful optical and electrical properties. The less well-known sub-class of porphyrin diacids has been used in this work to construct an ionic hybrid organic-inorganic material in combination with a halogenidometalate anion. The resulting compound, $[H_6TPyP][BiCl_6]_2$ (1) (TPyP = tetra(4-pyridyl)porphyrin) has been obtained via a facile solution based synthesis in single crystalline form. The material exhibits a broad photoluminescence emission band between 650 and 850 nm at room temperature. Single crystals of $[H_6TPyP][BiCl_6]_2$ show a photocurrent in the fA and a much higher dark current in the nA range. They also display an unexpected reversible color change upon wetting with different liquids. This phenomenon has been investigated with optical spectroscopy, SEM, XPS and NEXAFS techniques, showing that a surface-based structural coloration effect is the source of the color change. This stands in contrast to other materials where structural coloration typically has to be introduced through elaborate, multi-step processes or the use of natural templates. Additionally, it underscores the potential of self-assembly of porphyrinic hybrid compounds in the fabrication of materials with unusual optical properties

Sense-making strategies in explorative intelligence analysis of network evolutions

Visualising how social networks evolve is important in intelligence analysis in order to detect and monitor issues, such as emerging crime patterns or rapidly growing groups of offenders. It remains an open research question how this type of information should be presented for visual exploration. To get a sense of how users work with different types of visualisations, we evaluate a matrix and a node-link diagram in a controlled thinking aloud study. We describe the sense-making strategies that users adopted during explorative and realistic tasks. Thereby, we focus on the user behaviour in switching between the two visualisations and propose a set of nine strategies. Based on a qualitative and quantitative content analysis we show which visualisation supports which strategy better. We find that the two visualisations clearly support intelligence tasks and that for some tasks the combined use is more advantageous than the use of an individual visualisation

Everolimus after failure of one prior VEGF-targeted therapy in metastatic renal cell carcinoma : Final results of the MARC-2 trial

MARC-2, a prospective, multicenter phase IV trial, aimed to investigate clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus after failure of one initial vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy and to identify subgroups benefiting most, based on clinical characteristics and biomarkers. Patients with clear cell mRCC failing one initial VEGFR-TKI received everolimus until progression or unacceptable toxicity. Primary endpoint was 6-month progression-free survival rate (6moPFS). Secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. Between 2011 and 2015, 63 patients were enrolled. Median age was 65.4 years (range 43.3-81.1). 6moPFS was 39.3% (95% confidence interval [CI], 27.0-51.3) overall, 54.4% (95% CI, 35.2-70.1) vs 23.7% (95% CI, 10.5-39.9) for patients aged ≥65 vs 25 vs ≤25 kg/m2. A Cox proportional hazards model confirmed a longer PFS for patients aged ≥65 years (hazard ratio [HR] 0.46; 95% CI, 0.26-0.80) and a longer OS for patients with BMI >25 kg/m2 (HR 0.36; 95% CI, 0.18-0.71). Median PFS and median OS were 3.8 months (95% CI, 3.2-6.2) and 16.8 months (95% CI, 14.3-24.3). ORR was 7.9% and disease control rate was 60.3%. No new safety signals emerged. Most common adverse events were stomatitis (31.7%), fatigue (31.7%), and anemia (30.2%). One patient died from treatment-related upper gastrointestinal hemorrhage. Everolimus remains a safe and effective treatment option for mRCC patients after one prior VEGFR-TKI therapy. Patients aged ≥65 years and patients with BMI >25 kg/m2 benefited most