Aggregation of α-synuclein is kinetically controlled by intramolecular diffusion

We hypothesize that the first step of aggregation of disordered proteins, such as α-synuclein, is controlled by the rate of backbone reconfiguration. When reconfiguration is fast, bimolecular association is not stable, but as reconfiguration slows, association is more stable and subsequent aggregation is faster. To investigate this hypothesis, we have measured the rate of intramolecular diffusion in α-synuclein, a protein involved in Parkinson's disease, under solvent conditions that accelerate or decelerate aggregation. Using the method of tryptophan-cysteine (Trp-Cys) quenching, the rate of intramolecular contact is measured in four different loops along the chain length. This intrinsically disordered protein is highly diffusive at low temperature at neutral pH, when aggregation is slow, and compacts and diffuses more slowly at high temperature or low pH, when aggregation is rapid. Diffusion also slows with the disease mutation A30P. This work provides unique insights into the earliest steps of α-synuclein aggregation pathway and should provide the basis for the development of drugs that can prevent aggregation at the initial stage.     

The physical basis of fabrication of amyloid-based hydrogels by lysozyme

The fabrication of amyloid-based hydrogels has attracted remarkable attention within the field of materials science and technology. These materials have a multitude of potential applications in the biomaterials field such as developing scaffolds for tissue engineering, drug delivery and hygiene products. Despite the potential new applications of these materials, the physical nature of their assembly is not well understood. In this study, we have investigated how the conformation of the amyloid precursor state (I) is formed and correlated with the assembly of amyloid-based hydrogels. A transparent hydrogel was fabricated at pH 7.4 by cooling of the temperature-induced unfolded state of hen egg white lysozyme (HEWL). The completely unfolded state (U) at the gelation concentration of HEWL was obtained around 90 °C in the presence of tris(2-carboxyethyl)phosphine (TCEP), with a TCEP/HEWL molar ratio of 4 : 1. The characterization of the hydrogel showed that it was composed of an amyloid fibril-like material. The physical nature of its assembly was examined in detail and it was found that the hydrogel formation reaction was a three-step, four-states process (U → I → F → H). We concluded that the properties of the pre-molten globule state (I) of the protein correlated only with the fibrillation process, whereas the assembly of the fibrils into an hydrogel was found to be almost independent of the I state. Thus, the study presented here provides a complete biophysical insight into the pathway of lysozyme hydrogel assembly.

Schematic of heating- and cooling-induced transitions between HEWL states, and the subsequent formation of the hydrogel.     

Influence of thyroxine supplementation on orthodontically induced tooth movement and/or inflammatory root resorption: A systematic review

The role of thyroxine administration on orthodontically induced tooth movement and/or inflammatory root resorption remains unclear. The aim was to assess the influence of thyroxine administration on orthodontically induced tooth movement and/or inflammatory root resorption. The study protocol was registered in PROSPERO (CRD42020164151). An electronic search of indexed databases was conducted without time or language restrictions up to and including May 2020. The following eligibility criteria were imposed: (a) original prospective controlled clinical studies and/or experimental studies on animal models; (b) subjects undergoing orthodontic therapy with fixed appliances; (c) presence of a control group [orthodontic tooth movement without thyroxine administration]; and (d) intervention: orthodontic tooth movement with thyroxine administration. Review articles, commentaries, letters to the editor, case reports/series, studies with no control group, cross-sectional studies, retrospective studies and studies where thyroxine was administered along with other interventions such as calcitonin and prostaglandins were excluded. Quality of available evidence and risk of bias within studies were assessed. Any disagreements were resolved via consensus discussions. Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 8 animal studies were included. Four studies reported that thyroxine administration increases the rate of orthodontic tooth movement; 3 studies did not show a significant difference. Three studies showed that thyroxine administration decreases orthodontically induced inflammatory root resorption; 2 studies found no significant difference. The risk of bias among studies was high. In conclusion, the influence of thyroxine administration on orthodontic tooth movement and/or orthodontically induced inflammatory root resorption in animal models remains unclear.     

Identification of a ternary protein-complex as a therapeutic target for K-Ras-dependent colon cancer

A cancer phenotype is driven by several proteins and targeting a cluster of functionally interdependent molecules should be more effective for therapeutic intervention. This is specifically important for Ras-dependent cancer, as mutated (MT) Ras is non-druggable and targeting its interaction with effectors may be essential for therapeutic intervention. Here, we report that a protein-complex activated by the Ras effector p38γ MAPK is a novel therapeutic target for K-Ras-dependent colon cancer. Unbiased proteomic screening and immune-precipitation analyses identified p38γ interaction with heat shock protein 90 (Hsp90) and K-Ras in K-Ras MT, but not wild-type (WT), colon cancer cells, indicating a role of this complex in Ras-dependent growth. Further experiments showed that this complex requires p38γ and Hsp90 activity to maintain MT, but not WT, K-Ras protein expression. Additional studies demonstrated that this complex is activated by p38γ-induced Hsp90 phosphorylation at S595, which is important for MT K-Ras stability and for K-Ras dependent growth. Of most important, pharmacologically inhibition of Hsp90 or p38γ activity disrupts the complex, decreases K-Ras expression, and selectively inhibits the growth of K-Ras MT colon cancer in vitro and in vivo. These results demonstrated that the p38γ-activated ternary complex is a novel therapeutic target for K-Ras-dependent colon cancer.     

Adenosine A3 Receptor: A Promising Therapeutic Target in Cardiovascular Disease

Cardiovascular complications are one of the major factors for early mortality in the present worldwide scenario and have become a major challenge in both developing and developed nations. It has thus become of immense importance to look for different therapeutic possibilities and treatments for the growing burden of cardiovascular diseases. Recent advancements in research have opened various means for better understanding of the complication and treatment of the disease. Adenosine receptors have become tool of choice in understanding the signaling mechanism which might lead to the cardiovascular complications. Adenosine A3 receptor is one of the important receptor which is extensively studied as a therapeutic target in cardiovascular disorder. Recent studies have shown that A₃AR is involved in the amelioration of cardiovascular complications by altering the expression of A₃AR. This review focuses towards the therapeutic potential of A₃AR involved in cardiovascular disease and it might help in better understanding of mechanism by which this receptor may prove useful in improving the complications arising due to various cardiovascular diseases. Understanding of A₃AR signaling may also help to develop newer agonists and antagonists which might be prove helpful in the treatment of cardiovascular disorder.     

Readiness of obstetric professionals to inform parents regarding potential outcome of premature infants

Parents often regard obstetric professionals as an important source of information regarding prematurity. However, there is no information regarding the readiness of these obstetric professionals to inform expectant parents of the potential outcomes of premature infants. Using a self-report questionnaire, we determined the knowledge of obstetric professionals regarding outcomes of premature infants, and gauged their confidence in providing this information to expectant parents. Some 50% of obstetric professionals reported that they 'struggle to answer parental questions' regarding premature infants. The majority of obstetric professionals correctly identified potential morbidities of prematurity, but compared to neonatal professionals, they were less likely to discuss this information with parents. When they do provide information to parents, obstetric professionals were least likely to discuss neurological morbidities. Our study has identified an important barrier to the effective transfer of neonatal outcomes information to expectant parents. This limitation requires further investigation and intervention.