Total synthesis and structural assignment of Curvicollide C and derivatives of Fusaequisin A

(–)-Curvicollide C, a polyketide metabolite isolated from the mycoparasitic fungus Podospora curvicolla (left, Illinois 2004), shows striking structural similarity to (–)-Fusaequisin A, isolated from the endophytic fungus Fusarium equiseti (right, Cameroon 2013). As these fungi originate from different habitats and remote geographic locations, and, as they also differ in their morphological characteristics and phylogenetic classification the question arises why these fungi produce secondary metabolites of close structural relationship. In both cases the relative configuration was only partially elucidated while the absolute configuration remained unknown. The central heterocycles were determined to exhibit an all-trans configuration. This inspired us to initiate a research project aiming towards the total synthesis of both natural products, also because the unique combination of structural characteristics, imposed a synthetic challenge. Herein we report the first total synthesis of (+)-Curvicollide C and of a non-natural diastereomer of Fusaequisin A. Cross-metathesis and Julia–Kocienski olefination were chosen as the key coupling steps resulting in three retrosynthetic fragments, namely the Western, the Central, and the Eastern fragment. The synthesis was desined to rely on late-stage coupling of the configurationally and constitutionally customizable Western and Eastern fragements with the Central fragment of defined absolute configuration. The resulting highly modular synthesis provided access to a collection of five individually synthesized diastereomers of Curvicollide C, which enabled the full structural assignment of Curvicollide C by comparative NMR spectroscopic analysis.Der polyketide Metabolit (–)-Curvicollid C, welcher aus dem mycoparasitären Pilz Podospora curvicolla (links, Illinois 2004) isoliert wurde, zeigt eine auffällige strukturelle Ähnlichkeit zu (–)-Fusaequisin A. Dieser Metabolit wurde aus dem endophytischem Pilz Fusarium equiseti (rechts, Cameroon 2013) gewonnen. Da die beiden genannten Pilze aus unterschiedlichen biologischen Habitaten und geographischen Lagen stammen und sich zudem in ihren morphologischen Charakteristka und ihrer phylogenetischen Klassifikation unterscheiden stellt sich die Frage warum diese Pilze Sekundärmetabolite mit einem derart hohen strukturellen Verwandschaftsgrad bilden. Für beide Naturstoffe wurde die relative Konfiguration nur teilweise aufgeklärt und die absolute Konfiguration verblieb unbekannt. Den zentralen Heterozyklen wurde eine all-trans Konfiguration zugeordnet. Die unvollständige Strukturaufklärung forderte uns heraus ein Forschungsprojekt mit dem Ziel der Totalsynthese beider Naturstoffe anzugehen. Zudem sahen wir eine synthetische Herausforderung in der einzigartigen Kombination von strukturellen Charakterisika der beiden Naturstoffe. Im Folgenden berichten wir über die Totalsynthese von (+)-Curvicollid C sowie eines nicht natürlichen Diastereomers von Fusaequisin A. Als zentrale Verknüpfungsschritte wurden eine Kreuzmetathese und eine Olefinierung gewählt, wobei drei retrosynthetische Fragmente resultierten, welche im Folgenden als West-, Zentral- und Ost-Fragment bezeichnet werden. Die Synthese wurde aufbauend auf der Idee geplant, die Verknüpfungen der Fragmente auf einer möglichst späten Stufe durchzuführen, wobei das West- und Ost-Fragment in ihrer Konfiguration und Konstitution flexibel anpassbar sein sollten und das Zentral-Fragment in einer festgelegten absoluten Konfiguration vorliegt. Die resultierende modulare Synthese ermöglichte den Zugang zu einer Kollektion von fünf einzeln synthetisierten Diastereomeren von Curvicollid C. Durch vergleichende NMR Analyse dieser Diastereomere konnte schließlich eine zuverlässige Strukturaufklärung von Curvicollid C erzielt werden

Selfishness versus functional cooperation in a stochastic protocell model

How to design an "evolvable" artificial system capable to increase in complexity? Although Darwin's theory of evolution by natural selection obviously offers a firm foundation, little hope of success seems to be expected from the explanatory adequacy of modern evolutionary theory, which does a good job at explaining what has already happened but remains practically helpless at predicting what will occur. However, the study of the major transitions in evolution clearly suggests that increases in complexity have occurred on those occasions when the conflicting interests between competing individuals were partly subjugated. This immediately raises the issue about "levels of selection" in evolutionary biology, and the idea that multi-level selection scenarios are required for complexity to emerge. After analyzing the dynamical behaviour of competing replicators within compartments, we show here that a proliferation of differentiated catalysts and/or improvement of catalytic efficiency of ribozymes can potentially evolve in properly designed artificial cells. Experimental evolution in these systems will likely stand as beautiful examples of artificial adaptive systems, and will provide new insights to understand possible evolutionary paths to the evolution of metabolic complexity

Secukinumab demonstrated sustained retention, effectiveness and safety in a real-world setting in patients with moderate-to-severe plaque psoriasis: long-term results from an interim analysis of the SERENA study.

Randomized controlled trials of secukinumab have shown sustained efficacy and a favourable safety profile in multiple manifestations of psoriatic disease. To assess the long-term, real-world retention, effectiveness and safety of secukinumab in routine clinical practice for the treatment of moderate-to-severe plaque-type psoriasis (PsO). SERENA (CAIN457A3403) is a large, ongoing, longitudinal, observational study conducted at 438 sites and 19 countries for an expected duration of up to 5 years in adult patients with moderate-to-severe PsO, psoriatic arthritis and ankylosing spondylitis. Patients received ≥16 weeks of secukinumab treatment before enrolment. This interim analysis presents data from PsO patients, who were enrolled in the study between October-2016 and October-2018 and were observed for ≥2 years. In total, 1756 patients (67.3% male) with a mean age of 48.4 years and body mass index of 28.8 kg/m <sup>2</sup> were included in the analysis. The secukinumab treatment retention rates after 1, 2 and 3 years in the study were 88.0%, 76.4% and 60.5%, respectively. Of the 648 patients who discontinued the study, the most common reasons included lack of efficacy (42.6%), adverse event (17.4%), physician decision (12.2%) and subject decision (11.6%). Mean ± SD absolute PASI was 21.0 ± 13.0 at the start of treatment (n = 1,564). At baseline, the mean ± SD PASI score reduced to 2.6 ± 4.8 and remained low at Year 1 (2.3 ± 4.3), Year 2 (1.9 ± 3.6) and Year 3 (1.9 ± 3.5). The safety profile of secukinumab during the SERENA study was consistent with its known safety profile, with no new safety signals reported. Particularly, low rates of inflammatory bowel disease (0.3%; Incidence Rate [IR]:0.15), candida infections (3.1%; IR:1.43) and MACE (0.9%; IR:0.37) were observed. Secukinumab showed high treatment persistence, sustained effectiveness and a favourable safety profile up to 3 years of follow-up in the real-world population of PsO patients observed in SERENA

Exponential Replication of Patterns in the Signal Tile Assembly Model

Chemical self-replicators are of considerable interest in the field of nanomanufacturing and as a model for evolution. We introduce the problem of self-replication of rectangular two-dimensional patterns in the practically motivated Signal Tile Assembly Model (STAM) [9]. The STAM is based on the Tile Assembly Model (TAM) which is a mathematical model of self-assembly in which DNA tile monomers may attach to other DNA tile monomers in a programmable way. More abstractly, four-sided tiles are assigned glue types to each edge, and self-assembly occurs when singleton tiles bind to a growing assembly, if the glue types match and the glue binding strength exceeds some threshold. The signal tile extension of the TAM allows signals to be propagated across assemblies to activate glues or break apart assemblies. Here, we construct a pattern replicator that replicates a two-dimensional input pattern over some fixed alphabet of size φ with O(φ) tile types, O(φ) unique glues, and a signal complexity of O(1). Furthermore, we show that this replication system displays exponential growth in n, the number of replicates of the initial patterned assembly

Error thresholds for self- and cross-specific enzymatic replication

The information content of a non-enzymatic self-replicator is limited by Eigen's error threshold. Presumably, enzymatic replication can maintain higher complexity, but in a competitive environment such a replicator is faced with two problems related to its twofold role as enzyme and substrate: as enzyme, it should replicate itself rather than wastefully copy non-functional substrates, and as substrate it should preferably be replicated by superior enzymes instead of less-efficient mutants. Because specific recognition can enforce these propensities, we thoroughly analyze an idealized quasispecies model for enzymatic replication, with replication rates that are either a decreasing (self-specific) or increasing (cross-specific) function of the Hamming distance between the recognition or "tag" sequences of enzyme and substrate. We find that very weak self-specificity suffices to localize a population about a master sequence and thus to preserve its information, while simultaneous localization about complementary sequences in the cross-specific case is more challenging. A surprising result is that stronger specificity constraints allow longer recognition sequences, because the populations are better localized. Extrapolating from experimental data, we obtain rough quantitative estimates for the maximal length of the recognition or tag sequence that can be used to reliably discriminate appropriate and infeasible enzymes and substrates, respectively.Comment: 23 pages, 7 figures; final version as publishe

Theoretical analysis of cross-validation for estimating the risk of the k-Nearest Neighbor classifier

The present work aims at deriving theoretical guaranties on the behavior of some cross-validation procedures applied to the $k$-nearest neighbors ($k$NN) rule in the context of binary classification. Here we focus on the leave-$p$-out cross-validation (L$p$O) used to assess the performance of the $k$NN classifier. Remarkably this L$p$O estimator can be efficiently computed in this context using closed-form formulas derived by \cite{CelisseMaryHuard11}. We describe a general strategy to derive moment and exponential concentration inequalities for the L$p$O estimator applied to the $k$NN classifier. Such results are obtained first by exploiting the connection between the L$p$O estimator and U-statistics, and second by making an intensive use of the generalized Efron-Stein inequality applied to the L$1$O estimator. One other important contribution is made by deriving new quantifications of the discrepancy between the L$p$O estimator and the classification error/risk of the $k$NN classifier. The optimality of these bounds is discussed by means of several lower bounds as well as simulation experiments

Templated Synthesis of Peptide Nucleic Acids via Sequence-Selective Base-Filling Reactions

The templated synthesis of nucleic acids has previously been achieved through the backbone ligation of preformed nucleotide monomers or oligomers. In contrast, here we demonstrate templated nucleic acid synthesis using a base-filling approach in which individual bases are added to abasic sites of a peptide nucleic acid (PNA). Because nucleobase substrates in this approach are not self-reactive, a base-filling approach may reduce the formation of nontemplated reaction products. Using either reductive amination or amine acylation chemistries, we observed efficient and selective addition of each of the four nucleobases to an abasic site in the middle of the PNA strand. We also describe the addition of single nucleobases to the end of a PNA strand through base filling, as well as the tandem addition of two bases to the middle of the PNA strand. These findings represent an experimental foundation for nonenzymatic information transfer through base filling.Chemistry and Chemical Biolog