Development of Alpha-Synuclein protein model against therapeutic aspects of Parkinson's disease.

JOURNAL/ijpha/04.03/01363791-202456010-00007/figure1/v/2024-03-07T095025Z/r/image-tiff Parkinson's disease (PD) is the most common neurodegenerative disease caused by the steady depletion of dopamine in the striatum due to the loss of dopaminergic neurons. Most of the current therapeutics work on rebuilding the striatal dopamine level through oral administration of levodopa which stops the symptoms of PD. But there is a long-term motor complication with these dopamine precursors. Moreover, no preventive treatment is available for PD. Thus, before finding a therapeutic treatment for PD, it is necessary to first understand the basic cause of PD. Moreover, alpha-synuclein oligomerization can be the major factor in PD. From the UniProt database, protein information was extracted, and the model was designed by homology modeling technique and validated by the model validation server. Hence, the designed model has 96.5% most favored region and 0% disallowed region. Therefore, the model is stable based on RC plot parameters.

Rho-dependent termination enables cellular pH homeostasis.

The termination factor Rho, an ATP-dependent RNA translocase, preempts pervasive transcription processes, thereby rendering genome integrity in bacteria. Here, we show that the loss of Rho function raised the intracellular pH to >8.0 in Escherichia coli. The loss of Rho function upregulates tryptophanase-A (TnaA), an enzyme that catabolizes tryptophan to produce indole, pyruvate, and ammonia. We demonstrate that the enhanced TnaA function had produced the conjugate base ammonia, raising the cellular pH in the Rho-dependent termination defective strains. On the other hand, the constitutively overexpressed Rho lowered the cellular pH to about 6.2, independent of cellular ammonia levels. Since Rho overexpression may increase termination activities, the decrease in cellular pH could result from an excess H+ ion production during ATP hydrolysis by overproduced Rho. Furthermore, we performed in vivo termination assays to show that the efficiency of Rho-dependent termination was increased at both acidic and basic pH ranges. Given that the Rho level remained unchanged, the alkaline pH increases the termination efficiency by stimulating Rho's catalytic activity. We conducted the Rho-mediated RNA release assay from a stalled elongation complex to show an efficient RNA release at alkaline pH, compared to the neutral or acidic pH, that supports our in vivo observation. Whereas acidic pH appeared to increase the termination function by elevating the cellular level of Rho. This study is the first to link Rho function to the cellular pH homeostasis in bacteria. IMPORTANCE The current study shows that the loss or gain of Rho-dependent termination alkalizes or acidifies the cytoplasm, respectively. In the case of loss of Rho function, the tryptophanase-A enzyme is upregulated, and degrades tryptophan, producing ammonia to alkalize cytoplasm. We hypothesize that Rho overproduction by deleting its autoregulatory DNA portion increases termination function, causing excessive ATP hydrolysis to produce H+ ions and cytoplasmic acidification. Therefore, this study is the first to unravel a relationship between Rho function and intrinsic cellular pH homeostasis. Furthermore, the Rho level increases in the absence of autoregulation, causing cytoplasmic acidification. As intracellular pH plays a critical role in enzyme function, such a connection between Rho function and alkalization will have far-reaching implications for bacterial physiology.

Cosmetic iris implants - double edge sword.

Iris implants were originally described as an option to treat photophobia and glare associated with aniridia, coloboma, corectopia or any other causes of acquired or congenital iris defects. They are not designed to be used in healthy phakic eyes and not approved by regulatory bodies anywhere in the world for cosmesis. However, widespread publicity and the compulsive need for beautification has popularised the use of these implants illicitly. Implantation into phakic eyes causes mechanical irritation of angle structures leading to chronic inflammation, pigment dispersion, prolonged endothelial cell loss and compression of the trabecular meshwork. The consequences are dire, leading to presentation of such patients with serious complications involving the cornea, angle, and lens. Here we give an extensive review of available literature on cosmetic iris implants and also describe a case with bilateral cosmetic iris implants (New-ColorIris). The patient presented with corneal decompensation, glaucoma, and cataract in both eyes, seven years after the implantation and was successfully managed with explantation of the device followed by a DMEK Triple procedure.

A novel biodegradable polymer scaffold for in vitro growth of corneal epithelial cells.

The shortage of donor corneal tissue worldwide has led to extensive research for alternate corneal equivalents utilizing tissue engineering methods. We conducted experiments using Poly D, L lactic acid polymer along with a copolymer (Eudragit) in varying concentrations to create a biodegradable scaffold suitable for in vitro growth of corneal epithelial stem cells. It was found that stable, spherical, and porous microparticles can be prepared by combining PDLLA and Eudragit RL100 polymers in the ratio of 90:10 and 70:30. The microparticles can then be fused to form scaffold membranes with porous architecture and good water retention capacity at room temperature using methanol, which can withstand handling during transplantation procedures. The scaffolds made using a 70:30 ratio were found to be suitable for the promotion of growth of laboratory corneal epithelial stem cell lines (SIRC cell lines). This innovation can pave way for further developments in corneal stem cell research and growth, thus providing for viable laboratory-derived corneal substitutes.