ACS Omega最新文献

Importance: Advancing precision psychiatry, where treatments are based on an individual's biology rather than solely their clinical presentation, requires attention to several key attributes for any candidate biomarker. These include test-retest reliability, sensitivity to relevant neurophysiology, cost-effectiveness, and scalability. Unfortunately, these issues have not been systematically addressed by biomarker development efforts that use common neuroimaging tools like magnetic resonance imaging (MRI) and electroencephalography (EEG). Here, the critical barriers that neuroimaging methods will need to overcome to achieve clinical relevance in the near to intermediate term are examined.

Observations: Reliability is often overlooked, which together with sensitivity to key aspects of neurophysiology and replicated predictive utility, favors EEG-based methods. The principal barrier for EEG has been the lack of large-scale data collection among multisite psychiatric consortia. By contrast, despite its high reliability, structural MRI has not demonstrated clinical utility in psychiatry, which may be due to its limited sensitivity to psychiatry-relevant neurophysiology. Given the prevalence of structural MRIs, establishment of a compelling clinical use case remains its principal barrier. By contrast, low reliability and difficulty in standardizing collection are the principal barriers for functional MRI, along with the need for demonstration that its superior spatial resolution over EEG and ability to directly image subcortical regions in fact provide unique clinical value. Often missing, moreover, is consideration of how these various scientific issues can be balanced against practical economic realities of psychiatric health care delivery today, for which embedding economic modeling into biomarker development efforts may help direct research efforts.

Conclusions and relevance: EEG seems most ripe for near- to intermediate-term clinical impact, especially considering its scalability and cost-effectiveness. Recent efforts to broaden its collection, as well as development of low-cost turnkey systems, suggest a promising pathway by which neuroimaging can impact clinical care. Continued MRI research focused on its key barriers may hold promise for longer-horizon utility.

Clinical trials revealed that pioglitazone (PGZ) and dapagliflozin (DGZ) not only maintain normal blood glucose levels but also reduce complications of diabetes mellitus. To meet the demand for simultaneous measurement of these drugs in fixed combinations, an optimized and green UPLC method is required. The present study utilized Design of Experiments (DoE) software to optimize analytical parameters for simultaneous drug analysis. The method was validated for its linearity, accuracy, and precision. Furthermore, the drug content was estimated in different pharmaceutical dosage forms. Finally, Analytical Greenness (AGREE) software was utilized to assess the environmental sustainability of the optimized UPLC method. Drugs were successfully separated using optimized conditions on the C18 Acquity BEH column (2.1 mm × 100 mm, 1.7 μm) at a temperature of 45 °C. The mobile phase consisted of ethanol and 9 mM ammonium formate buffer (43.7:56.3), with elution carried out at a flow rate of 0.246 mL/min. The optimized method showed excellent linearity (R ² > 0.999), accuracy (92.45-109.25%), and good precision (RSD < 6.27%) for both drugs. In addition, the optimized UPLC method was able to determine the drug content within the marketed pharmaceutical dosage form accurately. The developed UPLC method also prioritized eco-friendliness by using green solvents to minimize the negative impact on the environment. The green UPLC method provides a reliable and accurate approach to estimate PGZ and DGZ in a fixed diabetes treatment combination. It promotes sustainable lab practices and paves the way for analytical methods for new dose combinations.

CO₂ injection into coal seams not only enhances coalbed methane (CBM) extraction but also allows for CO₂ sequestration. Microwave irradiation is considered to be an effective technology to enhance CBM extraction. In this paper, the effects of microwave irradiation and supercritical CO₂ immersion on the pore structure of low-rank coals were investigated by scanning electron microscopy (SEM), mercury-in-pressure (MIP), low-temperature nitrogen adsorption (LTN₂GA), and carbon dioxide isothermal adsorption/desorption (CO₂IA/D) of coal samples. The results showed that the macropores and micropores of the coal samples were more developed after microwave irradiation. After carbon dioxide immersion, the coal samples showed huge fissures, and the meso- and micropores were reduced. In contrast, microwave-assisted carbon dioxide not only reduced the specific surface area in the meso- and microporous stages and decreased the adsorption sites of methane but also enhanced the pore connectivity in the macroporous stage instead of the appearance of huge fissures. This study illustrates the potential of microwave-assisted supercritical carbon dioxide for enhanced coalbed methane extraction and carbon dioxide sequestration.

The tumor suppressor protein p53 is among the most commonly mutated proteins across a variety of cancer types. Notably, the p53 R175H mutation ranks as one of the most prevalent hotspot mutations. Proteolysis-targeting chimeras (PROTACs) represent a class of bifunctional molecules capable of harnessing the cellular ubiquitin-proteasome pathway to facilitate targeted protein degradation. Despite the potential of PROTACs, limited research has been directed toward the degradation of the p53-R175H mutant protein. In this study, we developed a series of peptide-based PROTACs, leveraging known peptide ligands for both the p53-R175H mutation and the E3 ubiquitin ligase VHL. Our findings indicate that one of these peptide-based PROTACs is capable of directing the p53-R175H protein to the proteasome for degradation within a recombinant expression system. Moreover, by synthesizing a fusion peptide PROTAC molecule that incorporates a membrane-penetrating peptide, we have demonstrated its ability to traverse cellular membranes and subsequently reduce the levels of the p53-R175H mutant protein. Importantly, the degradation of p53-R175H was found to mitigate the cellular migration and invasion. In summary, our study introduces a novel class of protein degraders and establishes a foundational framework for the therapeutic management of cancers associated with p53 mutations.

Acyclovir (ACV) is a vital treatment for herpes simplex (HSV) and varicella-zoster virus (VZV) infections that inhibit viral DNA polymerase. Phosphoramidate ProTides-ACV, a promising technology, circumvents the reliance on thymidine kinase (TK) for activation. Twelve novel single isomers of phosphoramidate ProTide-ACV were synthesized. Successful isomer separation was achieved, emphasizing the importance of single isomers in medical advancements. The enzymatic hydrolysis kinetics of the synthesized compounds were investigated by using carboxypeptidase Y (CPY). The results revealed a faster conversion for the isomer Rp- than for the Sp-diastereomer. Hydrolysis experiments confirmed steric hindrance effects, particularly with the tert-butyl and isopropyl groups. Molecular modeling elucidated the mechanisms of hydrolysis, supporting the results of the experiments. This research sheds light on the potential of phosphoramidate ProTides-ACV, bridging the gap in understanding their biological and metabolic properties, while supporting future investigations into anti-HSV activity. Preliminary screening revealed that three of the four single isomers demonstrated superior antiviral efficacy against wild-type HSV-1 compared to acyclovir, with isomer 24a ultimately reducing the viral yield at 200 μM. These findings emphasize the importance of isolating racemic ACV-ProTides as pure single isomers for future drug development.

A stimulus-responsive indole-based hydrogen bonding switch is reported, which enables off-on activation of transmembrane ion transport in response to photo- and redox triggers. This is achieved by alkylation of an indole-based anionophore, preorganized through intramolecular hydrogen bonding, with o-nitrobenzyl and azobenzene cages. This renders the anionophore inactive through formation of a six-membered intramolecular hydrogen bonding interaction and locking of the anion binding protons. Decaging with biologically relevant light and redox stimuli leads to efficient activation of anion transport across lipid bilayer membranes by unlocking the hydrogen bond donors, such that they are now available for anion binding and transport.