Collagenated Porcine Heterologous Bone Grafts: Histomorphometric Evaluation of Bone Formation Using Different Physical Forms in a Rabbit Cancellous Bone Model

Collagenated porcine-derived bone graft materials exhibit osteoconductive properties and the development of different formulations intends to enhance bone regeneration. This study aims to evaluate bone healing in a rabbit cancellous bone defect in response to grafting with different physicochemical forms of heterologous porcine bone. Twenty-six adult male New Zealand White rabbits received two critical size femoral bone defects per animal (n = 52), each randomly assigned to one of the five tested materials (Apatos, Gen-Os, mp3, Putty, and Gel 40). Animals were sacrificed at 15- and 30-days post-surgery. Qualitative and quantitative (new bone, particle and connective tissue percentages) histological analyses were performed. Histomorphometry showed statistically significant differences in all evaluated parameters between mp3 and both Putty and Gel 40 groups, regardless of the timepoint (p < 0.05). Moreover, statistical differences were observed between Apatos and both Putty (p = 0.014) and Gel 40 (p = 0.007) groups, at 30 days, in regard to particle percentage. Within each group, regarding new bone formation, mp3 showed significant differences (p = 0.028) between 15 (40.93 ± 3.49%) and 30 (52.49 ± 11.04%) days. Additionally, intragroup analysis concerning the percentage of particles revealed a significant reduction in particle occupied area from 15 to 30 days in mp3 and Gen-Os groups (p = 0.009). All mp3, Gen-Os and Apatos exhibited promising results in terms of new bone formation, thus presenting suitable alternatives to be used in bone regeneration.     

Adsorption Site Regulation to Guide Atomic Design of Ni–Ga Catalysts for Acetylene Semi-Hydrogenation

Atomic regulation of metal catalysts has emerged as an intriguing yet challenging strategy to boost product selectivity. Here, we report a density functional theory-guided atomic design strategy for the fabrication of a NiGa intermetallic catalyst with completely isolated Ni sites to optimize acetylene semi-hydrogenation processes. Such Ni sites show not only preferential acetylene π-adsorption, but also enhanced ethylene desorption. The characteristics of the Ni sites are confirmed by multiple characterization techniques, including aberration-corrected high-resolution scanning transmission electron microscopy and X-ray absorption spectrometry measurements. The superior performance is also confirmed experimentally against a Ni₅Ga₃ intermetallic catalyst with partially isolated Ni sites and against a Ni catalyst with multi-atomic ensemble Ni sites. Accordingly, the NiGa intermetallic catalyst with the completely isolated Ni sites shows significantly enhanced selectivity to ethylene and suppressed coke formation.     

Cacaoidin,First Member of the New Lanthidin RiPP Family

Lantibiotics are ribosomally synthesized and post-translationally modified peptides (RiPPs) characterized by the presence of lanthionine or methyllanthionine rings and their antimicrobial activity. Cacaoidin, a novel glycosylated lantibiotic, was isolated from a Streptomyces cacaoi strain and fully characterized by NMR, mass spectrometry, chemical derivatization approaches and genome analysis. The new molecule combines outstanding structural features, such as a high number of d -amino acids, an uncommon glycosylated tyrosine residue and an unprecedented N,N-dimethyl lanthionine. This latter feature places cacaoidin within a new RiPP family located between lanthipeptides and linaridins, here termed lanthidins. Cacaoidin displayed potent antibacterial activity against Gram-positive pathogens including Clostridium difficile. The biosynthetic gene cluster showed low homology with those of other known lanthipeptides or linaridins, suggesting a new RiPP biosynthetic pathway.     

Protective role of estrogen against excessive erythrocytosis in Monge’s disease

Monge’s disease (chronic mountain sickness (CMS)) is a maladaptive condition caused by chronic (years) exposure to high-altitude hypoxia. One of the defining features of CMS is excessive erythrocytosis with extremely high hematocrit levels. In the Andean population, CMS prevalence is vastly different between males and females, being rare in females. Furthermore, there is a sharp increase in CMS incidence in females after menopause. In this study, we assessed the role of sex hormones (testosterone, progesterone, and estrogen) in CMS and non-CMS cells using a well-characterized in vitro erythroid platform. While we found that there was a mild (nonsignificant) increase in RBC production with testosterone, we observed that estrogen, in physiologic concentrations, reduced sharply CD235a⁺ cells (glycophorin A; a marker of RBC), from 56% in the untreated CMS cells to 10% in the treated CMS cells, in a stage-specific and dose-responsive manner. At the molecular level, we determined that estrogen has a direct effect on GATA1, remarkably decreasing the messenger RNA (mRNA) and protein levels of GATA1 (p < 0.01) and its target genes (Alas2, BclxL, and Epor, p < 0.001). These changes result in a significant increase in apoptosis of erythroid cells. We also demonstrate that estrogen regulates erythropoiesis in CMS patients through estrogen beta signaling and that its inhibition can diminish the effects of estrogen by significantly increasing HIF1, VEGF, and GATA1 mRNA levels. Taken altogether, our results indicate that estrogen has a major impact on the regulation of erythropoiesis, particularly under chronic hypoxic conditions, and has the potential to treat blood diseases, such as high altitude severe erythrocytosis.Subject terms: Haematopoietic stem cells, Myeloproliferative disease     

Structured Space-Sphere Point Processes and K-Functions

Methodology and Computing in Applied Probability - This paper concerns space-sphere point processes, that is, point processes on the product space of $\mathbb {R}^{d}$ (the d-dimensional Euclidean...     

De Novo Design of Selective Quadruplex–Duplex Junction Ligands and Structural Characterisation of Their Binding Mode: Targeting the G4 Hot-Spot

Targeting the interface between DNA quadruplex and duplex regions by small molecules holds significant promise in both therapeutics and nanotechnology. Herein, a new pharmacophore is reported, which selectively binds with high affinity to quadruplex–duplex junctions, while presenting a poorer affinity for G-quadruplex or duplex DNA alone. Ligands complying with the reported pharmacophore exhibit a significant affinity and selectivity for quadruplex–duplex junctions, including the one observed in the HIV-1 LTR-III sequence. The structure of the complex between a quadruplex–duplex junction with a ligand of this family has been determined by NMR methods. According to these data, the remarkable selectivity of this structural motif for quadruplex–duplex junctions is achieved through an unprecedented interaction mode so far unexploited in medicinal and biological chemistry: the insertion of a benzylic ammonium moiety into the centre of the partially exposed G-tetrad at the interface with the duplex. Further decoration of the described scaffolds with additional fragments opens up the road to the development of selective ligands for G-quadruplex-forming regions of the genome.     

Setting the Foundations of Aqueous Three-Phase Systems (A3PS) in the Quest for a Rational Design

This work presents the first in-depth study of Aqueous Three-Phase Systems (A3PS) with the main purpose of unveiling their behaviour, hence contributing to the development of this new field. Thus, a complete definition of a quaternary system was carried through by describing all the regions in detail to represent them later on in a regular-tetrahedral diagram. The three aqueous faces of the tetrahedron demonstrated an undeviating influence in the segregation capacity. Furthermore, a method for comparing Aqueous Biphasis Systems (ABS) immiscibilities was set up in order to allow the evaluation and detection of the “limiting ABS” for the three-phase region. Finally, all this information was compiled and utilised to obtain a new strategy for an A3PS rational design, which can be applied with ABS libraries or in an experimental approach. In this sense, this strategy represents an undoubted advance towards future studies and development of A3PS, as this sequential application of the constructed knowledge is assumed to save time and resources.     

A Light-Triggerable Nanoparticle Library for the Controlled Release of Non-Coding RNAs

RNA-based therapies offer a wide range of therapeutic interventions including the treatment of skin diseases; however, the strategies to efficiently deliver these biomolecules are still limited due to obstacles related to the cellular uptake and cytoplasmic delivery. Herein, we report the synthesis of a triggerable polymeric nanoparticle (NP) library composed of 160 formulations, presenting physico-chemical diversity and differential responsiveness to light. Six formulations were more efficient (up to 500 %) than commercially available lipofectamine in gene-knockdown activity. These formulations showed differential internalization by skin cells and the endosomal escape was rapid (minutes range). The NPs were effective in the release of siRNA and miRNA. Acute skin wounds treated with the top hit NP complexed with miRNA-150-5p healed faster than wounds treated with scrambled miRNA. Light-activatable NPs offer a new strategy to topically deliver non-coding RNAs.