Antibody binding increases the flexibility of the prion protein

Prion diseases are associated with the conversion of the cellular prion protein (PrP) into a pathogenic conformer (PrPSc). A proposed therapeutic approach to avoid the pathogenic transformation is to develop antibodies that bind to PrP and stabilize its structure. POM1 and POM6 are two monoclonal antibodies that bind the globular domain of PrP and have different biological responses, i.e., trigger neurotoxicity mimicking prion infections (POM1) or prevent neurotoxicity (POM6). The crystal structures of PrP in complex with the two antibodies show similar epitopes which seems inconsistent with the opposite phenotypes. Here, we investigate the influence of the POM1 and POM6 antibodies on the flexibility of the mouse PrP by molecular dynamics simulations. The simulations reveal that the POM6/PrP interface is less stable than the POM1/PrP interface, ascribable to localized polar mismatches at the interface, despite the former complex having a larger epitope than the latter. In the presence of any of the two antibodies, the flexibility of the globular domain increases everywhere except for the β1-α1 loop in the POM1/PrP complex which suggests the involvement of this loop in the pathological conversion. The secondary structure of PrP is preserved whereas the polar interactions involving residues Glu146, Arg156 and Arg208 are modified upon antibody binding

THE BEHAVIOR OF SOME COTTON (GOSSYPIUM HIRSUTUM) GENOTYPES UNDER SANDY SOIL CONDITIONS IN SOUTHERN OLTENIA

This study follows the behaviour of seven genotypes of cotton (Gossypium hirsutum), cultivated on the sandy soils of Dăbuleni, with the aim of diversifying the range of plants tolerant to climatic factors in southern Oltenia. Observation of vegetative characteristics such as plant height, number of sympodia, number of flowers in the first decade of flowering and quantitative characteristics such as boll weight, fibre weight, seed weight and number of seeds / plant were the object of the study. Research on cotton plant development was correlated with climatic data recorded by the weather station of Dăbuleni RDSPCS, during the growing season from plant sowing in the field to boll formation. Following the study and showing positive results, The Beli-Lom genotype stood out in terms of flowering yield and fibre percentage, and the Cirpan-539 and Beli-Iskar genotypes had positive vegetative growth yield

The attachment of α-synuclein to a fiber:A coarse-grain approach

We present simulations of the amyloidogenic core of α-synuclein, the protein causing Parkinson’s disease, as a short chain of coarse-grain patchy particles. Each particle represents a sequence of about a dozen amino acids. The fluctuating secondary structure of this intrinsically disordered protein is modelled by dynamic variations of the shape and interaction characteristics of the patchy particles, ranging from spherical with weak isotropic attractions for the disordered state to spherocylindrical with strong directional interactions for a β-sheet. Flexible linkers between the particles enable sampling of the tertiary structure. This novel model is applied here to study the growth of an amyloid fibril, by calculating the free energy profile of a protein attaching to the end of a fibril. The simulation results suggest that the attaching protein readily becomes trapped in a mis-folded state, thereby inhibiting further growth of the fibril until the protein has readjusted to conform to the fibril structure, in line with experimental findings and previous simulations on small fragments of other proteins

Some Peculiarities of the Xanthium italicum Moretti Germination Process

AbstractFruit formations of Xanthium italicum were gathered from plants, sand and a river bank. They were put in germination conditions to observe how this process takes places and what the seedlings’ growth rate is in the early stages, until the first true leaf appears. Data were processed by variance analysis; using the Duncan test, the correlations between germination and seedlings’ growth in X. italicum and the place of sampling the anthodiums was highlighted. The fruit formations’ harvesting site influences the germination process, the finding being statistically significant; between the length of hypocotyl and cotyledons there is a distinct correlation, statistically significant (r = 0.908) regardless of the place of harvest

Nutrigenetics: unravelling the genetic contributions to obesity, cardiovascular diseases, and diabetes mellitus

In this review, we aim to explore the field of nutrigenetics and its potential impact on obesity, cardiovascular diseases, and diabetes mellitus. Current dietary approaches in nutritional science often overlook the individual’s genetic profile, limiting the effectiveness of personalized diets. Nutrigenetics aims to incorporate genetic data into nutritional interventions to optimize disease prevention and treatment strategies. Regarding obesity, genetic factors, including multiple genes and alleles, influence body weight and predisposition to obesity. The FTO and MC4R genes, for example, have been linked to weight gain and appetite regulation. Similarly, genetic variations in the APO-A and APO-E gene families affect lipid metabolism and susceptibility to cardiovascular diseases. Genetic variations in genes such as MTHFR and PPAR-γ2 have been associated with increased cardiovascular risk, while dietary factors, such as the consumption of fruits and vegetables, can reduce the likelihood of developing these diseases. In diabetes mellitus, both type 1 and type 2, genetic factors also play a significant role. Genes like IGF2BP2 and PRKAA2 impact insulin resistance and glucose metabolism. Although nutrigenetics is still a developing field, it has the potential to revolutionize personalized nutrition plans and improve health outcomes

Silybins inhibit human IAPP amyloid growth and toxicity through stereospecific interactions

Type 2 Diabetes is a major public health threat, and its prevalence is increasing worldwide. The abnormal accumulation of islet amyloid polypeptide (IAPP) in pancreatic β-cells is associated with the onset of the disease. Therefore, the design of small molecules able to inhibit IAPP aggregation represents a promising strategy in the development of new therapies. Here we employ in vitro, biophysical, and computational methods to inspect the ability of Silybin A and Silybin B, two natural diastereoisomers extracted from milk thistle, to interfere with the toxic self-assembly of human IAPP (hIAPP). We show that Silybin B inhibits amyloid aggregation and protects INS-1 cells from hIAPP toxicity more than Silybin A. Molecular dynamics simulations revealed that the higher efficiency of Silybin B is ascribable to its interactions with precise hIAPP regions that are notoriously involved in hIAPP self-assembly i.e., the S20-S29 amyloidogenic core, H18, the N-terminal domain, and N35. These results highlight the importance of stereospecific ligand-peptide interactions in regulating amyloid aggregation and provide a blueprint for future studies aimed at designing Silybin derivatives with enhanced drug-like properties. Keywords: Aggregation; Diabetes; Inhibitors; Molecular dynamics; Peptid

Thermostable designed ankyrin repeat proteins (DARPins) as building blocks for innovative drugs

Designed ankyrin repeat proteins (DARPins) are antibody mimetics with high and mostly unexplored potential in drug development. By using in silico analysis and a rationally guided Ala scanning, we identified position 17 of the N-terminal capping repeat to play a key role in overall protein thermostability. The melting temperature of a DARPin domain with a single full-consensus internal repeat was increased by 8 °C to 10 °C when Asp17 was replaced by Leu, Val, Ile, Met, Ala, or Thr. We then transferred the Asp17Leu mutation to various backgrounds, including clinically validated DARPin domains, such as the vascular endothelial growth factor-binding domain of the DARPin abicipar pegol. In all cases, these proteins showed improvements in the thermostability on the order of 8 °C to 16 °C, suggesting the replacement of Asp17 could be generically applicable to this drug class. Molecular dynamics simulations showed that the Asp17Leu mutation reduces electrostatic repulsion and improves van-der-Waals packing, rendering the DARPin domain less flexible and more stable. Interestingly, this beneficial Asp17Leu mutation is present in the N-terminal caps of three of the five DARPin domains of ensovibep, a SARS-CoV-2 entry inhibitor currently in clinical development, indicating this mutation could be partly responsible for the very high melting temperature (>90 °C) of this promising anti-COVID-19 drug. Overall, such N-terminal capping repeats with increased thermostability seem to be beneficial for the development of innovative drugs based on DARPins. Keywords: DARPin; N-terminal capping repeat; abicipar pegol; designed ankyrin repeat protein; drug development; drug engineering; ensovibep; molecular dynamics; thermostabilit