Adduct formation between ternary Pt(II)-amino acid-aromatic diimine complexes and flavin mononucleotide and its effect on redox properties

Adduct formation of ternary Pt(II) complexes composed of an amino acid and an aromatic diimine, [Pt(A)(DA)] (A = glycinate (Gly), alaninate (Ala), valinate, or arginine (Arg); DA = 2,2′-bipyridine (bpy) or 1,10-phenanthroline (phen)), with flavin mononucleotide (FMN) and anthraquinone-2-sulfonate (AQS) were investigated by spectroscopic, X-ray diffraction, and electrochemical methods. The Pt(II) complexes formed 1:1 [Pt(A)(DA)]-FMN adducts by stacking with the aromatic moiety of FMN, and the stability constants, log K, for the systems with [Pt(A)(phen)] (A = Gly, Ala, and Arg) and [Pt(Arg)(bpy)] were determined to be 2.83(8)-3.42(6) from ¹H NMR spectra at 25 °C in D₂O (I = var.). The structure of the adduct [Pt(Ala)(phen)](AQS) (1) was determined by X-ray analysis to involve a π-π stacking interaction between coordinated phen and AQS with the distance of 3.400(7) Å and a hydrogen bond between the sulfonate moiety of AQS and the amino group of coordinated Ala. Cyclic voltammetry of the 1:1 [Pt(A)(DA)]-FMN systems in a phosphate buffer (pH 7.0) showed that the potentials, E_1/2, for the two-electron redox process of FMN shifted to higher values by 18-31 mV as compared with the value for free FMN.     

Secondary structure and phylogenetic analysis of the internal transcribed spacers 1 and 2 of bush crickets (Orthoptera: Tettigoniidae: Barbitistini)

We inferred secondary structure models of the internal transcribed spacers (ITS) 1 and 2 of bush crickets using a combined comparative and thermodynamic approach. The inferred secondary structure models were used to account for interdependency of interacting nucleotides in a phylogenetic analysis of the bush cricket genus Poecilimon. Our analysis indicates that the two previously reported conformational structures (i.e., hairpin and ring) of ITS2 are likely to fold in bush crickets as well and that both predicted structures are similar to those proposed for other eukaryotes. Comparing predicted ITS1 secondary structure models proved to be difficult because of substantial variation in their nucleotide sequence length. Our study revealed that the phylogenetic signal of ITS1 and ITS2 is largely congruent with that preserved in the mitochondrial genes 16S rRNA, tRNA‐Val and 12S rRNA. The phylogenetic signal in both the nuclear and the mitochondrial genome question the monophyly of the genus Poecilimon: species of the genera Poecilimonella, Parapoecilimon, Polysarcus and Phonochorion consistently cluster within Poecilimon.     

Ichnosystematics of the Lower Permian Invertebrate Traces from the Collio and Mt. Luco Basins (North Italy)

The Lower Permian ichnofauna in the Collio Formation (Artinskian) in the Val Trompia (Brescian Prealps, North Italy) has been studied for a long time, but the studies have focused mainly on vertebrate prints. In this study, the invertebrate ichnofauna of the Collio Formation, and in the epiclastites of the Monte Luco Formation (Artinskian) cropping out in the Monte Luco area (Trentino Alto Adige region), is systematically analyzed for the first time. This ichnocoenosis consists of: Permichnium isp., Paleohelcura tridactyla, Diplichnites gouldi (Types A and B), Diplopodichnus biformis, Circulichnis montanus, Helminthopsis hieroglyphica, Gordia marina, Acripes cf. multiformis, Cruziana cf. problematica, Cochlichnus anguineus, Palaeophycus tubularis, Planolites isp. and ?Scoyenia isp. The ichnoassociation from the Collio Formation belongs to the Scoyenia ichnofacies, while that from the Mt. Luco Formation belongs to the Mermia ichnofacies. The latter, because of the lack of complete data, can be linked only to one of several submersion phases of the intravolcanic basin and is not referred to the complete continental Permian sequence in this zone. The composition of the ichnoassociation here analysed is similar to those of other European (especially France and Germany) and extra-European areas (especially North America and Argentina).     

BDNF VAL66MET polymorphism and memory decline across the spectrum of Alzheimer's disease

The brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism has been shown to moderate the extent to which memory decline manifests in preclinical Alzheimer's disease (AD). To date, no study has examined the relationship between BDNF and memory in individuals across biologically confirmed AD clinical stages (i.e., Aβ+). We aimed to understand the effect of BDNF on episodic memory decline and clinical disease progression over 126 months in individuals with preclinical, prodromal and clinical AD. Participants enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study who were Aβ + (according to positron emission tomography), and cognitively normal (CN; n = 238), classified as having mild cognitive impairment (MCI; n = 80), or AD (n = 66) were included in this study. Cognition was evaluated at 18 month intervals using an established episodic memory composite score over 126 months. We observed that in Aβ + CNs, Met66 was associated with greater memory decline with increasing age and were 1.5 times more likely to progress to MCI/AD over 126 months. In Aβ + MCIs, there was no effect of Met66 on memory decline or on disease progression to AD over 126 months. In Aβ + AD, Val66 homozygotes showed greater memory decline, while Met66 carriers performed at a constant and very impaired level. Our current results illustrate the importance of time and disease severity to clinicopathological models of the role of BDNF Val66Met in memory decline and AD clinical progression. Specifically, the effect of BDNF on memory decline is greatest in preclinical AD and reduces as AD clinical disease severity increases.     

Reprogramming Escherichia coli pyruvate-forming reaction towards chorismate derivatives production

Microbial metabolic pathway engineering is a potent strategy used worldwide to produce aromatic compounds. We drastically rewired the primary metabolic pathway of Escherichia coli to produce aromatics and their derivatives. The metabolic pathway of E. coli was compartmentalized into the production and energy modules. We focused on the pyruvate-forming reaction in the biosynthesis pathway of some compounds as the reaction connecting those modules. E. coli strains were engineered to show no growth unless pyruvate was synthesized along with the compounds of interest production. Production of salicylate and maleate was demonstrated to confirm our strategy's versatility. In maleate production, the production, yield against the theoretical yield, and production rate reached 12.0 g L⁻¹, 67%, and up to fourfold compared to that in previous reports, respectively; these are the highest values of maleate production in microbes to our knowledge. The results reveal that our strategy strongly promotes the production of aromatics and their derivatives.     

Molecular dynamics simulation study of AG10 and tafamidis binding to the Val122Ile transthyretin variant

Molecular dynamics (MD) simulations were used to investigate the binding of four ligands to the Val122Ile mutant of the protein transthyretin. Dissociation, misfolding, and subsequent aggregation of mutated transthyretin proteins are associated with the disease Familial Amyloidal Cardiomyopathy. The ligands investigated were the drug candidate AG10 and its decarboxy and N-methyl derivatives along with the drug tafamidis. These ligands bound to the receptor in two halogen binding pockets (HBP) designated AB and A’B’. Inter-ligand distances, solvent accessible surface areas, root mean squared deviation measurements, and extracted structures showed very little change in the AG10 ligands' conformations or locations within the HBP during the MD simulation. In addition, the AG10 ligands experienced stable, two-point interactions with the protein by forming hydrogen bonds with Ser-117 residues in both the AB and A’B’ binding pockets and Lysine-15 residues found near the surface of the receptor. Distance measurements showed these H-bonds formed simultaneously during the MD simulation. Removal of the AG10 carboxylate functional group to form decarboxy-AG10 disrupted this two-point interaction causing the ligand in the AB pocket to undergo a conformational change during the MD simulation. Likewise, addition of a methyl group to the AG10 hydrazone functional group also disrupted the two-point interaction by decreasing hydrogen bonding interactions with the receptor. Finally, MD simulations showed that the tafamidis ligands experienced fewer hydrogen bonding interactions than AG10 with the protein receptor. The tafamidis ligand in pocket A’B’ was also found to move deeper into the HBP during the MD simulation.     

Synthesis of a novel conformationally restricted Val-Phe dipeptidomimetic.

A method for the synthesis of (3(R,S),6S,11b(R,S))-1,3,4,6,7,11b-hexahydro-4-oxo-3-phthalimidopyrido[2,1-a]isoquinoline-6-carboxylic acid 2 as a new conformationally restricted dipeptidomimetic of Val-Phe is reported. It involved cyclisation via an intramolecular electrophilic addition at the reactive bridgehead carbon. This new scaffold can be used as a building block in the preparation of libraries of peptidomimetics.     

European Dendroecological Fieldweek (EDF) 2021 in Val Müstair,Switzerland: International education and research during the pandemic

The European Dendroecological Fieldweek (EDF) is a one-week course that takes place every year at varying locations in Europe according to the principle “Bring tree-ring research to the people”. The EDF welcomes early-career to advanced researchers, but also forest service and other federal agency employees and private people interested in tree-ring sciences from all over the world. It encompasses a large spectrum of dendrochronological field, laboratory and data analysis methods and scientific fields including climatology, ecology, physiology, geomorphology and archaeology. Multiple scales of observations from the individual cell to the ecosystem level and from seasonal to multi-centennial periods are covered. Work on mini research projects in topic groups alternates with keynote lectures and individual participants’ presentations.As one of the first in-person tree-ring meetings since the start of the COVID-19 pandemic the 31st EDF was held in summer 2021 in Val Müstair, Switzerland. Topics included i) Tree age and climate sensitivity of a relict, old-growth Scots pine stand, ii) Blue intensity-based climate sensitivity of Norway spruce growth, iii) Tree rings as indicators of grey larch budmoth outbreaks, iv) Growth of larch trees along an abandoned irrigation channel, v) Wood anatomical characteristics of two alpine creeping shrub species, and vi) Historical dating of a stable and a residential house. Alongside with their educational value these projects allowed novel insight into the age structure and growth dynamics of the sub-alpine forests and beyond in the valley and provided valuable outcome to the local stakeholders such as the Nature Park Biosfera Val Müstair, the local forest service and the public of Val Müstair.Under hindered conditions due to the pandemic, the 31st EDF still demonstrated its strength as an international educational and interdisciplinary scientific field and lab course, combining teaching with the application of cutting-edge technologies.