General cross-coupling reactions with adaptive dynamic homogeneous catalysis.

Cross-coupling reactions are among the most important transformations in modern organic synthesis1-3. Although the range of reported (het)aryl halides and nucleophile coupling partners is very large considering various protocols, the reaction conditions vary considerably between compound classes, necessitating renewed case-by-case optimization of the reaction conditions4. Here we introduce adaptive dynamic homogeneous catalysis (AD-HoC) with nickel under visible-light-driven redox reaction conditions for general C(sp2)-(hetero)atom coupling reactions. The self-adjustive nature of the catalytic system allowed the simple classification of dozens of various classes of nucleophiles in cross-coupling reactions. This is synthetically demonstrated in nine different bond-forming reactions (in this case, C(sp2)-S, Se, N, P, B, O, C(sp3, sp2, sp), Si, Cl) with hundreds of synthetic examples under predictable reaction conditions. The catalytic reaction centre(s) and conditions differ from one another by the added nucleophile, or if required, a commercially available inexpensive amine base.

Neutrophil Extracellular Traps Initiate Gallstone Formation.

The presence of gallstones (cholelithiasis) is a highly prevalent and severe disease and one of the leading causes of hospital admissions worldwide. Due to its substantial health impact, we investigated the biological mechanisms that lead to the formation and growth of gallstones. We show that gallstone assembly essentially requires neutrophil extracellular traps (NETs). We found consistent evidence for the presence of NETs in human and murine gallstones and describe an immune-mediated process requiring activation of the innate immune system for the formation and growth of gallstones. Targeting NET formation via inhibition of peptidyl arginine deiminase type 4 or abrogation of reactive oxygen species (ROS) production, as well as damping of neutrophils by metoprolol, effectively inhibit gallstone formation in vivo. Our results show that after the physicochemical process of crystal formation, NETs foster their assembly into larger aggregates and finally gallstones. These insights provide a feasible therapeutic concept to prevent cholelithiasis in patients at risk.

A stable hippocampal code in freely flying bats.

Neural activity in the hippocampus is known to reflect how animals move through an environment1,2. Although navigational behaviour may show considerable stability3-6, the tuning stability of individual hippocampal neurons remains unclear7-12. Here we used wireless calcium imaging to longitudinally monitor the activity of dorsal CA1 hippocampal neurons in freely flying bats performing highly reproducible flights in a familiar environment. We find that both the participation and the spatial selectivity of most neurons remain stable over days and weeks. We also find that apparent changes in tuning can be largely attributed to variations in the flight behaviour of the bats. Finally, we show that bats navigating in the same environment under different room lighting conditions (lights on versus lights off) exhibit substantial changes in flight behaviour that can give the illusion of neuronal instability. However, when similar flight paths are compared across conditions, the stability of the hippocampal code persists. Taken together, we show that the underlying hippocampal code is highly stable over days and across contexts if behaviour is taken into account.

DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer.

TAp63α, a homolog of the p53 tumor suppressor, is a quality control factor in the female germline. Remarkably, already undamaged oocytes express high levels of the protein, suggesting that TAp63α's activity is under tight control of an inhibitory mechanism. Biochemical studies have proposed that inhibition requires the C-terminal transactivation inhibitory domain. However, the structural mechanism of TAp63α inhibition remains unknown. Here, we show that TAp63α is kept in an inactive dimeric state. We reveal that relief of inhibition leads to tetramer formation with ∼20-fold higher DNA affinity. In vivo, phosphorylation-triggered tetramerization of TAp63α is not reversible by dephosphorylation. Furthermore, we show that a helix in the oligomerization domain of p63 is crucial for tetramer stabilization and competes with the transactivation domain for the same binding site. Our results demonstrate how TAp63α is inhibited by complex domain-domain interactions that provide the basis for regulating quality control in oocytes.

Tracking the habituation of the event-related EEG potential in automatic change detection using an auditory two-tone oddball paradigm.

The mismatch negativity and the P3a of the event-related EEG potential reflect the electrocortical response to a deviant stimulus in a series of stimuli. Although both components have been investigated in various paradigms, these paradigms usually incorporate many repetitions of the same deviant, thus leaving open whether both components vary as a function of the deviant's position in a series of deviant stimuli-i.e. whether they are subject to qualitative/quantitative habituation from one instantiation of a deviant to the next. This is so because the detection of mismatch negativity/P3a in the event-related EEG potential requires an averaging over dozens or hundreds of stimuli, i.e. over many instantiations of the deviant per participant. The present study addresses this research gap. We used a two-tone oddball paradigm implementing only a small number of (deviant) stimuli per participant, but applying it to a large number of participants (n > 230). Our data show that the mismatch negativity amplitude exhibits no decrease as a function of the deviant's position in a series of (standard and) deviant stimuli. Importantly, only after the very first deviant stimulus, a distinct P3a could be detected, indicative of an orienting reaction and an attention shift, and thus documenting a dissociation of mismatch negativity and P3a.

Product Selectivity in Baeyer-Villiger Monooxygenase-Catalyzed Bacterial Alkaloid Core Structure Maturation.

Baeyer-Villiger monooxygenases (BVMOs) play crucial roles in the core-structure modification of natural products. They catalyze lactone formation by selective oxygen insertion into a carbon-carbon bond adjacent to a carbonyl group (Baeyer-Villiger oxidation, BVO). The homologous bacterial BVMOs, BraC and PxaB, thereby process bicyclic dihydroindolizinone substrates originating from a bimodular nonribosomal peptide synthetase (BraB or PxaA). While both enzymes initially catalyze the formation of oxazepine-dione intermediates following the identical mechanism, the final natural product spectrum diverges. For the pathway involving BraC, the exclusive formation of lipocyclocarbamates, the brabantamides, was reported. The pathway utilizing PxaB solely produces pyrrolizidine alkaloids, the pyrrolizixenamides. Surprisingly, replacing pxaB within the pyrrolizixenamide biosynthetic pathway by braC does not change the product spectrum to brabantamides. Factors controlling this product selectivity have remained elusive. In this study, we set out to solve this puzzle by combining the total synthesis of crucial pathway intermediates and anticipated products with in-depth functional in vitro studies on both recombinant BVMOs. This work shows that the joint oxazepine-dione intermediate initially formed by both BVMOs leads to pyrrolizixenamides upon nonenzymatic hydrolysis, decarboxylative ring contraction, and dehydration. Brabantamide biosynthesis is enzyme-controlled, with BraC efficiently transforming all the accepted substrates into its cognate final product scaffold. PxaB, in contrast, shows only considerable activity toward brabantamide formation for the substrate analog with a natural brabantamide-type side chain structure, revealing substrate-controlled product selectivity.

From the Iron Pentacarbonyl Cation to Heteroleptic η6-arene Carbonyls and bis-η6-arene Cations.

Partial ligand substitution at the iron pentacarbonyl radical cation generates novel half-sandwich complexes of the type [Fe(η6-arene)(CO)2]⋅+ (arene=1,3,5-tri-tert-butylbenzene, 1,3,5-trimethylbenzene, benzene and fluorobenzene). Of those, the bulkier 1,3,5-tri-tert-butylbenzene (mes*) derivative [Fe(mes*)(CO)2]⋅+ was fully characterized by XRD analysis, IR, NMR, cw-EPR, Mössbauer spectroscopy and cyclic voltammetry as the [Al(ORF)4]- (RF=C(CF3)3) salt. Chemical electronation, i. e., the single electron reduction, with decamethylferrocene generates neutral [Fe(mes*)(CO)2], whereas further deelectronation under CO-pressure leads to a dicationic three-legged [Fe(mes*)(CO)3]2+ salt with [Al(ORF)4]- counterion. The full substitution of the carbonyl ligands in [Fe(CO)5]⋅+[Al(ORF)4]- mainly resulted in disproportionation reactions, giving solid Fe(0) and the dicationic bis-arene salts [Fe(η6-arene)2]2+([Al(ORF)4]-)2 (arene=1,3,5-trimethylbenzene, benzene and fluorobenzene). Only by employing the very large fluoride bridged anion [F-{Al(ORF)3}2]-, it was possible to isolate an open shell bis-arene cation salt [Fe(C6H6)2]⋅+[F-{Al(ORF)3}2]-. The highly reactive cation was characterized by XRD analysis, cw-EPR, Mössbauer spectroscopy and cyclic voltammetry. The disproportionation of [Fe(C6H6)2]⋅+ salts to give solid Fe(0) and [Fe(C6H6)2]2+ salts was analyzed by a suitable cycle, revealing that the thermodynamic driving force for the disproportionation is a function of the size of the anion used and the polarity of the solvent.

Biosynthesis of cyanobacterin, a paradigm for furanolide core structure assembly.

The γ-butyrolactone motif is found in many natural signaling molecules and other specialized metabolites. A prominent example is the potent aquatic phytotoxin cyanobacterin, which has a highly functionalized γ-butyrolactone core structure. The enzymatic machinery that assembles cyanobacterin and structurally related natural products (herein termed furanolides) has remained elusive for decades. Here, we elucidate the biosynthetic process of furanolide assembly. The cyanobacterin biosynthetic gene cluster was identified by targeted bioinformatic screening and validated by heterologous expression in Escherichia coli. Full functional evaluation of the recombinant key enzymes in vivo and in vitro, individually and in concert, provided in-depth mechanistic insights into a streamlined C-C bond-forming cascade that involves installation of compatible reactivity at seemingly unreactive Cα positions of amino acid precursors. Our work extends the biosynthetic and biocatalytic toolbox for γ-butyrolactone formation, provides a general paradigm for furanolide biosynthesis and sets the stage for their targeted discovery, biosynthetic engineering and enzymatic synthesis.

Enzymatic assembly of the salinosporamide γ-lactam-ß-lactone anticancer warhead.

The marine microbial natural product salinosporamide A (marizomib) is a potent proteasome inhibitor currently in clinical trials for the treatment of brain cancer. Salinosporamide A is characterized by a complex and densely functionalized γ-lactam-ß-lactone bicyclic warhead, the assembly of which has long remained a biosynthetic mystery. Here, we report an enzymatic route to the salinosporamide core catalyzed by a standalone ketosynthase (KS), SalC. Chemoenzymatic synthesis of carrier protein-tethered substrates, as well as intact proteomics, allowed us to probe the reactivity of SalC and understand its role as an intramolecular aldolase/ß-lactone synthase with roles in both transacylation and bond-forming reactions. Additionally, we present the 2.85-Å SalC crystal structure that, combined with site-directed mutagenesis, allowed us to propose a bicyclization reaction mechanism. This work challenges our current understanding of the role of KS enzymes and establishes a basis for future efforts toward streamlined production of a clinically relevant chemotherapeutic.

Kinetically Controlled Site-Specific Self-assembly of Hairy Colloids.

The solvophobicity-driven directional self-assembly of polymer-coated gold nanorods is a well-established phenomenon. Yet, the kinetics of this process, the origin of site-selectivity in the self-assembly, and the interplay of (attractive) solvophobic brush interactions and (repulsive) electrostatic forces are not fully understood. Herein, we use a combination of time-resolved (vis/NIR) extinction spectroscopy and finite-difference time-domain (FDTD) simulations to determine conversion profiles for the assembly of gold nanorods with polystyrene shells of distinct thicknesses into their (tip-to-tip) self-assembled structures. In particular, we demonstrate that the assembly process is highly protracted compared with diffusion-controlled rates, and we find that the assembly rate varies for different thickness values of the polymer shell. Our findings were rationalized using coarse-grained molecular dynamics simulations, which also corroborated the tip-to-tip preference in the self-assembly process, albeit with a uniform polymer coating. Utilizing the knowledge of quantified conversion rates for distinct colloidal species, we designed coassembling systems with different brush thicknesses, featuring "narcissistic" self-sorting behavior. This provides new perspectives for high-level supracolloidal self-assembly.

Improving selection decisions with mating information by accounting for Mendelian sampling variances looking two generations ahead.

BACKGROUND: Breeding programs are judged by the genetic level of animals that are used to disseminate genetic progress. These animals are typically the best ones of the population. To maximise the genetic level of very good animals in the next generation, parents that are more likely to produce top performing offspring need to be selected. The ability of individuals to produce high-performing progeny differs because of differences in their breeding values and gametic variances. Differences in gametic variances among individuals are caused by differences in heterozygosity and linkage. The use of the gametic Mendelian sampling variance has been proposed before, for use in the usefulness criterion or Index5, and in this work, we extend existing approaches by not only considering the gametic Mendelian sampling variance of individuals, but also of their potential offspring. Thus, the criteria developed in this study plan one additional generation ahead. For simplicity, we assumed that the true quantitative trait loci (QTL) effects, genetic map and the haplotypes of all animals are known. RESULTS: In this study, we propose a new selection criterion, ExpBVSelGrOff, which describes the genetic level of selected grand-offspring that are produced by selected offspring of a particular mating. We compare our criterion with other published criteria in a stochastic simulation of an ongoing breeding program for 21 generations for proof of concept. ExpBVSelGrOff performed better than all other tested criteria, like the usefulness criterion or Index5 which have been proposed in the literature, without compromising short-term gains. After only five generations, when selection is strong (1%), selection based on ExpBVSelGrOff achieved 5.8% more commercial genetic gain and retained 25% more genetic variance without compromising inbreeding rate compared to selection based only on breeding values. CONCLUSIONS: Our proposed selection criterion offers a new tool to accelerate genetic progress for contemporary genomic breeding programs. It retains more genetic variance than previously published criteria that plan less far ahead. Considering future gametic Mendelian sampling variances in the selection process also seems promising for maintaining more genetic variance.

Running the gauntlet; flyway-wide patterns of pollutant exposure in blood of migratory shorebirds.

Shorebirds (order Charadriiformes) are among the world's most threatened avian taxa. Within the East Asian-Australasian Flyway (EAAF), a major threat to shorebirds' survival may be the gauntlet of pollution along the flyway. Metals, persistent organic pollutants (POPs), and per-/polyfluoroalkyl substances (PFASs) persist in the environment to the detriment of wildlife. In this study, we analysed element and PFAS concentrations in blood from 142 individuals across six species of Arctic-breeding migratory shorebirds with contrasting population trends, to discern species- and site-specific pollution differences, and determine how pollution correlated with population trends of EAAF shorebirds. Potential within-year pollution variations were investigated by blood-sampling birds at two sites, representing different points in the birds' annual migrations: staging in Taiwan on southward migrations and at non-breeding grounds in Western Australia (WA). Species' pollutant concentrations were compared to established population trends. Concentrations of potentially toxic elements were low in most individuals regardless of species. PFASs (range: <0.001-141 ng/g), Hg (<0.001-9910 ng/g) and Pb (<0.01-1210 ng/g) were higher in Taiwan than in WA (PFAS Taiwan median: 14.5 ng/g, WA median: 3.45 ng/g; Hg Taiwan: 338 ng/g, WA: 23.4 ng/g; Pb Taiwan: 36.8 ng/g, WA: 2.26 ng/g). Meanwhile As (range <0.001-8840 ng/g) and Se (290-47600 ng/g) were higher in WA than Taiwan (As Taiwan median: 500 ng/g, WA median: 1660 ng/g; Se Taiwan: 5490 ng/g, Se WA: 23700 ng/g). Nevertheless, pollutant concentrations in a subset of individuals may exceed sublethal effect thresholds (As, Se and PFASs). Finally, we found no consistent differences in pollution among species and demonstrated no correlation between pollution and population trends, suggesting pollution is likely not a major driver for population declines of EAAF shorebirds. However, ongoing and locally heavy environmental degradation and exposure to other contaminants not investigated here, such as POPs, warrants continued consideration when managing EAAF shorebird populations.

Stress and compulsive buying-shopping disorder: A scoping review.

INTRODUCTION: Theoretical frameworks of behavioral addictions mostly acknowledge the role of stress in the development and maintenance of these disorders, models of compulsive buying-shopping disorder (CBSD) however rarely incorporated stress. The association between stress and CBSD has not been reviewed yet. METHODS: A scoping review was conducted to evaluate empirical results on the association between stress and CBSD. A comprehensive search string was employed in three databases. RESULTS: 16 studies were included. Correlative studies suggested significant correlations between general perceived stress and CBSD symptom severity. Studies involving mean comparisons found higher general perceived stress levels in persons with problematic buying-shopping behavior/CBSD compared to control participants (large effects). Mixed results were found in studies involving regression/structural equation models and ecological momentary assessments. One study with a stress/negative mood induction observed more CBSD symptoms in a high stress group compared to a low stress group. DISCUSSION: The studies are heterogeneous concerning design, samples and measures. Only very few studies surpass the level of cross-sectional correlative data which limits the ability to draw clear conclusions. Future research should study the impact of experimentally induced stress on CBSD symptoms, examine the relationship between stress and CBSD longitudinally and assess objective stress markers.

70 Years - from DNA Double Helix via Approaching Systems Genomics to a Generalized Unified Evolution Theory.

70 Years - from DNA Double Helix via Approaching Systems Genomics to a Generalized Unified Evolution Theory.

Utilizing the Perfluoronaphthalene Radical Cation as a Selective Deelectronator to Access a Variety of Strongly Oxidizing Reactive Cations.

A selective deelectronation reagent with very high potential of +2.00 (solution)/+2.41 V (solid-state) vs. Fc+/0 and based on a room temperature stable perfluoronaphthalene (naphthaleneF) radical cation salt was developed and applied. The solid-state deelectronation of commercial naphthaleneF with [NO]+[F{Al(ORF)3}2]- generates [naphthaleneF]+⋅[F{Al(ORF)3}2]- (ORF=OC(CF3)3) in gram scale. Thermochemical analysis unravels the solid-state deelectronation potential of the starting [NO]+-reagent to be +2.34 V vs. Fc+/0 with [F{Al(ORF)3}2]- counterion, but only +1.14 V vs. Fc+/0 with the small [SbF6]- ion. Selective reactions demonstrate the selectivity of [naphthaleneF]+⋅ for deelectronation of a multitude of organ(ometall)ic molecules and elements in solution: providing the molecular structures of the acene dications [tetracene]2+, [pentacene]2+ or spectroscopic evidence for the carbonyl complex of the ferrocene dication [Fc(CO)]2+, the [P9]+ cation from white phosphorus, the solvent-free copper(I) salt starting from copper metal and the dicationic Fe(IV)-scorpionate complex [Fe(sc)2]2+.

Introduction to engineering the biosynthesis of fungal natural products.

Filamentous fungi are highly diverse eukaryotes that inhabit all known ecosystems on earth. Estimates suggest that more than 2 × 106 species are likely to exist, and analyses of typical fungal genomes suggest they harbour around 50 biosynthetic gene clusters on average. The biosynthetic potential of these organisms is thus vast. Fungi produce all the main classes of secondary metabolites, and numerous hybrid compounds. Many are highly useful in medicine such as the 'classic' special metabolites penicillins, cephalosporins, statins and mycophenolic acid, and new antimicrobial agents such as the pleuromutilins and enfumafungins that overcome specific patterns of resistance. Fungi differentiated from bacteria more than a billion years ago, so there has been plenty of time for uniquely fungal biosynthetic systems to evolve.

N2 Reduction versus H2 Evolution in a Molybdenum- or Tungsten-Based Small-Molecule Model System of Nitrogenase.

Molybdenum dinitrogen complexes have played a major role as catalytic model systems of nitrogenase. In comparison, analogous tungsten complexes have in most cases found to be catalytically inactive. Herein, a tungsten complex was shown to be supported by a pentadentate tetrapodal (pentaPod) phosphine ligand, under conditions of N2 fixation, primarily catalyzes the hydrogen evolution reaction (HER), in contrast to its Mo analogue, which catalytically mediates the nitrogen-reduction reaction (N2 RR). DFT calculations were employed to evaluate possible mechanisms and identify the most likely pathways of N2 RR and HER activities exhibited by Mo- and W-pentaPod complexes. Two mechanisms for N2 RR by PCET are considered, starting from neutral (M(0) cycle) and cationic (M(I) cycle) dinitrogen complexes (M=Mo, W). The latter was found to be energetically more favorable. For HER three scenarios are treated; that is, through bimolecular reactions of early M-Nx Hy intermediates, pure hydride intermediates or mixed M(H)(Nx Hy ) species.

The Rise of Structurally Anisotropic Plasmonic Janus Gold Nanostars.

Nanostructures intrinsically possessing two different structural or functional features, often called Janus nanoparticles, are emerging as a potential material for sensing, catalysis, and biomedical applications. Herein, we report the synthesis of plasmonic gold Janus nanostars (NSs) possessing a smooth concave pentagonal morphology with sharp tips and edges on one side and, contrastingly, a crumbled morphology on the other. The methodology reported herein for their synthesis - a single-step growth reaction - is different from any other Janus nanoparticle preparation involving either template-assisted growth or a masking technique. Interestingly, the coexistence of lower- and higher-index facets was found in these Janus NSs. The general paradigm for synthesizing gold Janus NSs was investigated by understanding the kinetic control mechanism with the combinatorial effect of all the reagents responsible for the structure. The optical properties of the Janus NSs were realized by corelating their extinction spectra with the simulated data. The size-dependent surface-enhanced Raman scattering (SERS) activity of these Janus NSs was studied with 1,4-BDT as the model analyte. Finite-difference time-domain simulations for differently sized particles revealed the distribution of electromagnetic hot-spots over the particles resulting in enhancement of the SERS signal in a size-dependent manner.

Tunable Macrocyclic Polyparaphenylene Nanolassos via Copper-Free Click Chemistry.

Deriving diverse compound libraries from a single substrate in high yields remains to be a challenge in cycloparaphenylene chemistry. In here, a strategy for the late-stage functionalization of shape-persistent alkyne-containing cycloparaphenylene has been explored using readily available azides. The copper-free [3+2]azide-alkyne cycloaddition provided high yields (>90 %) in a single reaction step. Systematic variation of the azides from electron-rich to -deficient shines light on how peripheral substitution influences the characteristics of the resulting adducts. We find that among the most affected properties are the molecular shape, the oxidation potential, excited state features, and affinities towards different fullerenes. Joint experimental and theoretical results are presented including calculations with the state-of-the-art, artificial intelligence-enhanced quantum mechanical method 1 (AIQM1).

Block Copolymer-Templated Au@CdSe Core-Satellite Nanostructures with Solvent-Dependent Optical Properties.

In the present work, we report the fabrication and characterization of well-defined core-satellite nanostructures. These nanostructures comprise block copolymer (BCP) micelles, containing a single gold nanoparticle (AuNP) in the core and multiple photoluminescent cadmium selenide (CdSe) quantum dots (QDs) attached to the micelle's coronal chains. The asymmetric polystyrene-block-poly(4-vinylpyridine) (PS-b-P4VP) BCP was employed to develop these core-satellite nanostructures in a series of P4VP-selective alcoholic solvents. The BCP micelles were first prepared in 1-propanol and subsequently mixed with AuNPs, followed by gradual addition of CdSe QDs. This method resulted in the development of spherical micelles that contained a PS/Au core and a P4VP/CdSe shell. These core-satellite nanostructures, developed in different alcoholic solvents, were further employed for the time-resolved photoluminescence analysis. It was found that solvent-selective swelling of the core-satellite nanostructures tunes the distance between the QDs and AuNPs and modulates their Förster resonance energy transfer (FRET) behavior. The average lifetime of the donor emission varied from 12.3 to 10.3 nanoseconds (ns) with the change in the P4VP-selective solvent within the core-satellite nanostructures. Furthermore, the distances between the donor and acceptor were also calculated using efficiency measurements and corresponding Förster distances. The resulting core-satellite nanostructures hold promising potential in various fields, such as photonics, optoelectronics, and sensors that utilize the FRET process.