The Congenital Cataract-Linked G61C Mutation Destabilizes γD-Crystallin and Promotes Non-Native Aggregation

γD-crystallin is one of the major structural proteins in human eye lens. The solubility and stability of γD-crystallin play a crucial role in maintaining the optical properties of the lens during the life span of an individual. Previous study has shown that the inherited mutation G61C results in autosomal dominant congenital cataract. In this research, we studied the effects of the G61C mutation on γD-crystallin structure, stability and aggregation via biophysical methods. CD, intrinsic and extrinsic fluorescence spectroscopy indicated that the G61C mutation did not affect the native structure of γD-crystallin. The stability of γD-crystallin against heat- or GdnHCl-induced denaturation was significantly decreased by the mutation, while no influence was observed on the acid-induced unfolding. The mutation mainly affected the transition from the native state to the intermediate but not that from the intermediate to the unfolded or aggregated states. At high temperatures, both proteins were able to form aggregates, and the aggregation of the mutant was much more serious than the wild type protein at the same temperature. At body temperature and acidic conditions, the mutant was more prone to form amyloid-like fibrils. The aggregation-prone property of the mutant was not altered by the addition of reductive reagent. These results suggested that the decrease in protein stability followed by aggregation-prone property might be the major cause in the hereditary cataract induced by the G61C mutation

Medium Chain Acylcarnitines Dominate the Metabolite Pattern in Humans under Moderate Intensity Exercise and Support Lipid Oxidation

Background: Exercise is an extreme physiological challenge for skeletal muscle energy metabolism and has notable health benefits. We aimed to identify and characterize metabolites, which are components of the regulatory network mediating the beneficial metabolic adaptation to exercise

Investigating Homology between Proteins using Energetic Profiles

Accumulated experimental observations demonstrate that protein stability is often preserved upon conservative point mutation. In contrast, less is known about the effects of large sequence or structure changes on the stability of a particular fold. Almost completely unknown is the degree to which stability of different regions of a protein is generally preserved throughout evolution. In this work, these questions are addressed through thermodynamic analysis of a large representative sample of protein fold space based on remote, yet accepted, homology. More than 3,000 proteins were computationally analyzed using the structural-thermodynamic algorithm COREX/BEST. Estimated position-specific stability (i.e., local Gibbs free energy of folding) and its component enthalpy and entropy were quantitatively compared between all proteins in the sample according to all-vs.-all pairwise structural alignment. It was discovered that the local stabilities of homologous pairs were significantly more correlated than those of non-homologous pairs, indicating that local stability was indeed generally conserved throughout evolution. However, the position-specific enthalpy and entropy underlying stability were less correlated, suggesting that the overall regional stability of a protein was more important than the thermodynamic mechanism utilized to achieve that stability. Finally, two different types of statistically exceptional evolutionary structure-thermodynamic relationships were noted. First, many homologous proteins contained regions of similar thermodynamics despite localized structure change, suggesting a thermodynamic mechanism enabling evolutionary fold change. Second, some homologous proteins with extremely similar structures nonetheless exhibited different local stabilities, a phenomenon previously observed experimentally in this laboratory. These two observations, in conjunction with the principal conclusion that homologous proteins generally conserved local stability, may provide guidance for a future thermodynamically informed classification of protein homology

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Dendrimers: A Platform For Novel Drug Delivery System

The review majorly based on four areas i.e., architecturing, synthesis, properties & applications of dendrimer. The dendrimers having unique architectural design of high degree of branching, multivalency, globular architecture and well defined molecular weight which distinguishesthis structure is unique and optimum nanocarriersin medical applications such as drug delivery, gene delivery, tumor therapy,diagnostic etc. It has some synthetic approaches lead to a dendritic architecture with properties complaisant to modification of shape, size, polarity,surface properties & internal structure.Nanoparticle drug delivery system is popular once are able to increase the stability and selectivity of therapeutic agents. The reticuloendothelial system (RES) uptake drug leakage, cytotoxicity, immunogenicity, hemolytic toxicity, hydrophobicity restrict the use of these nanostructure.And these problems are overcome by surface engineering the dendrimers such as, polyester dendrimer, citric acid dendrimer, argining dendrimer, glycol dendrimers, PEGlyated dendrimers, etc. The bioactive agents can be easily encapsulated in to the interior of the dendrimers and are chemically attached such as conjugated or physically absorbed onto the dendrimer surface,serving the desired properties of the carrier to the specific needs of active material and its therapeutic applications.In addition to supplying a multivalent backbone for drug attachment, dendrimers also provide access for various new polymer architectures that are potentially relevant to drug delivery applications

Analysis of Bank Soundness Level at Regional Development Bank of Bali for 2012 to 2021

The purpose of this study is to analyze the health level at RDB of Bali by using the Risk Based Bank Rating (RBBR) method. The RBBR method includes Risk Profile, Good Corporate Governance, Earnings, and Capital (RGEC). A quantitative descriptive approach was used to analyze. The variables in this study are the Risk Profile includes the ratio of Non Performing Loans (NPL) and Loan to Deposit Ratio (LDR), Good Corporate Governance (GCG) uses the composite value of GCG, Earnings includes the ratio of Return on Assets (ROA) and Net Interest Margin (NIM) and Capital includes the Capital Adequacy Ratio (CAR). Data were collected from annual reports for the period 2012 to 2021. The results showed that RDB of Bali obtained a composite rating of 2, which means the bank is in a healthy condition