Structure-based protein design with deep learning

Since the first revelation of proteins functioning as macromolecular machines through their three dimensional structures, researchers have been intrigued by the marvelous ways the biochemical processes are carried out by proteins. The aspiration to understand protein structures has fueled extensive efforts across different scientific disciplines. In recent years, it has been demonstrated that proteins with new functionality or shapes can be designed via structure-based modeling methods, and the design strategies have combined all available information — but largely piece-by-piece — from sequence derived statistics to the detailed atomic-level modeling of chemical interactions. Despite the significant progress, incorporating data-derived approaches through the use of deep learning methods can be a game changer. In this review, we summarize current progress, compare the arc of developing the deep learning approaches with the conventional methods, and describe the motivation and concepts behind current strategies that may lead to potential future opportunities.     

Impact of High Deductible Health Plans on Diabetes Care Quality and Outcomes: Systematic Review

ObjectiveTo provide a review of the impact of high deductible health plans (HDHPs) on the utilizations of services required for optimal management of diabetes and subsequent health outcomes.MethodsSystematic literature review of studies published between January 1, 2000, and May 7, 2021, was conducted that examined the impact of HDHP on diabetes monitoring (eg, recommended laboratory and surveillance testing), routine care (eg, ambulatory appointments), medication management (eg, medication initiation, adherence), and acute health care utilization (eg, emergency department visits, hospitalizations, incident complications).ResultsOf the 303 reviewed articles, 8 were relevant. These studies demonstrated that HDHPs lower spending at the expense of reduced high-value diabetes monitoring, routine care, and medication adherence, potentially contributing to the observed increases in acute health care utilization. Additionally, patient out-of-pocket costs for recommended screenings doubled, and total health care expenditures increased by 49.4% for HDHP enrollees compared with enrollees in traditional health plans. Reductions in disease monitoring and routine care and increases in acute health care utilization were greatest in lower-income patients. None of the studies examined the impact of HDHPs on access to diabetes self-management education, technology use, or glycemic control.ConclusionAlthough HDHPs reduce some health care utilization and costs, they appear to do so at the expense of limiting high-value care and medication adherence. Policymakers, providers, and payers should be more cognizant of the potential for negative consequences of HDHPs on patients’ health.     

Design,synthesis, characterization,antibacterial and antifungal activities of a novel class of 5,7-diaryl-4,4-dimethyl-4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3-selenadiazoles

Compound 26 is more potent against Escherichia coli. and 24 is more active against Staphylococcus aureus, β-Heamolytic streptococcus, Vibreo cholerae, Salmonella typhii, and Shigella flexneri than the standard drug ciprofloxacin. Moreover, of all the compounds tested, 26 is more effective against Aspergillus flavus and Mucor, than the standard drug fluconazole.     

High-Throughput Drug Screening Identifies a Potent Wnt Inhibitor that Promotes Airway Basal Stem Cell Homeostasis

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Structure of Cu2(indomethacin)4 and the reaction with superoxide in aprotic systems

The copper complex of indomethacin (1-(p-chlorobenzoyl)-5-methoxy-2-methyl-indole acetate), a common anti-inflammatory drug, was prepared and characterized. Crystal structure determination revealed the dimeric form of the 1:2 complex, namely Cu₂(indomethacin)₄ · L₂, in the unit cell. Suprisingly, the copper-copper distance (263 pm) was very close to metallic copper (256 pm). The two coordination sites in the copper-copper axis can be readily replaced by superoxide. An intriguing similarity to Cu₂(acetate)₄ was seen.Due to the lipophilic nature of the indomethacin ligand, this copper complex reacted with superoxide in aprotic solvents. The superoxide dismutating activity was successfully demonstrated in Me₂SO/water and acetonitrile/water mixtures using the nitro-blue tetrazolium assay and pulse radiolysis. The second-order rate constant of 6 · 10⁹ M^?1 · s^?1 in strictly aqueous systems dropped only slightly to 1.1 · 10⁹ M^?1 · s^?1 when aprotic solvents were used. This is the fastest rate constant ever observed for a copper-dependent dismutation of superoxide. The KO₂-induced lipid peroxidation in both erythrocytes and liver microsomes was suppressed by 70% in the presence of 1 · 10^?10 mol · ml^?1 of Cu₂(indomethacin)₄. The inhibitory action dropped to 25% when Cu₂Zn₂superoxide dismutase was employed. The formation of copper · indomethacin in rat serum after administration of indomethacin was shown in vitro and in vivo.     

Portrait of the Patient as a Young Man: An Exploration of the Use of Photographs in Hospital

The display of personal photographs in hospital is a common practice that has yet to be rigorously examined. The photographs displayed are subject to interpretation by the viewer and may lead to misunderstandings or miscommunication if clarification of meaning is not sought. This paper explores a range of possible meanings that the display of photographs in hospital may hold, based on a case study of a 15 year old boy hospitalised with a life threatening illness. Further research is needed into the actual meanings attributed to the display of photographs in hospital by patients and family members.     

Hybrid nanoreservoirs based on dextran-capped dendritic mesoporous silica nanoparticles for CD133-targeted drug delivery

In this study, the chemical features of dendritic mesoporous silica nanoparticles (DMSNs) provided the opportunity to design a nanostructure with the capability to intelligently transport the payload to the tumor cells. In this regard, doxorubicin (DOX)-encapsulated DMSNs was electrostatically surface-coated with polycarboxylic acid dextran (PCAD) to provide biocompatible dextran-capped DMSNs (PCAD-DMSN@DOX) with controlled pH-dependent drug release. Moreover, a RNA aptamer against a cancer stem cell (CSC) marker, CD133 was covalently attached to the carboxyl groups of DEX to produce a CD133-PCAD-DMSN@DOX. Then, the fabricated nanosystem was utilized to efficiently deliver DOX to CD133+ colorectal cancer cells (HT29). The in vitro evaluation in terms of cellular uptake and cytotoxicity demonstrated that the CD133-PCAD-DMSN@DOX specifically targets HT29 as a CD133 overexpressed cancer cells confirmed by flow cytometry and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay. The potentially promising intelligent-targeted platform suggests that targeted dextran-capped DMSNs may find impressive application in cancer therapy.     

Antibacterial Agents in Mediterranean Finfish Farming: A Synopsis of Drug Pharmacokinetics in Important Euryhaline Fish Species and Possible Environmental Implications

The literature pertaining to the use of registered antibacterial agents in Mediterranean finfish farming is reviewed, with an emphasis on the Greek fish-farming industry. This review provides a scientific resource dedicated to the design of future antibacterial dosing regimes in Mediterranean fish farming, where insufficient supporting information is currently available. This paper addresses the paucity in knowledge concerning pharmacokinetics and the efficacy and environmental impact of commonly used antibacterials needed to direct future research and promote good practices in the euryhaline fish farming industry. Several registered antibacterials are currently available for combating bacterial infections, including tetracyclines, (fluoro) quinolones, potentiated sulfa, penicillin and chloramphenicol derivatives. Based on the available data, oxytetracycline (OTC) and quinolone drugs (oxolinic acid – OA and flumequine – FLU) are the most widely used in Mediterranean aquaculture. As a result these drugs have received the most extensive studies, whereas, there is considerable paucity of reliable data on pharmacokinetic and the depletion characteristics of other drugs used, particularly potentiated sulfa, penicillin derivatives and florfenicol. We find there is incomplete data on drug efficacy and minimum inhibitory concentrations (MIC) for common antibacterials used against the major bacterial pathogens of Mediterranean fish species. Furthermore, a considerable lack of data on environmental drug concentrations around Mediterranean fish farms was also identified, highlighting the need for more extensive environmental studies to monitor contamination in environmental components i.e., water and sediment, and in non-target species (flora and fauna). Prudent selection and use of antibacterials can encourage lower dosage applications, enhance treatment efficacy, and help to minimize contamination of the environment. Selection of readily bioavailable drugs which have low environmental persistence, low aquatic toxicity and high antibacterial efficacy is advised, to reduce potential losses to the environment and associated toxic effects on target species and the development of bacterial resistance. Lack of present data made it impossible to provide thorough and accurate guidance on selection and use of antibacterials and approaches for minimizing environmental impacts for the treatment of major euryhaline aquaculture species.     

Optimization of pancreatic lipase inhibition by Cudrania tricuspidata fruits using response surface methodology

The fruits of Cudrania tricuspidata (Carr.) Bur. (Moraceae) significantly inhibited pancreatic lipase, which plays a key role in fat absorption. Optimization of extraction conditions with minimum pancreatic lipase activity and maximum yield was determined using response surface methodology with three-level-three-factor Box–Behnken design (BBD). Regression analysis showed a good fit of the experimental data and the optimal condition was obtained as ethanol concentration, 74.5%; temperature 61.9 °C and extraction time, 13.5 h. The pancreatic lipase activity and extraction yield under optimal conditions were found to be 65.5% and 54.0%, respectively, which were well matched with the predicted value of 65.8% and 47.1%. Further fractionation of C. tricuspidata extract resulted in the isolation of compound 1, which was identified as 5,7,4′-trihydroxy-6,8-diprenylisoflavone. It inhibited pancreatic lipase activity with IC₅₀ value of 65.0 μM. HPLC analysis suggested positive correlation between pancreatic lipase inhibition and 5,7,4′-trihydroxy-6,8-diprenylisoflavone of C. tricuspidata fruits.