Characterization of Opioid Agonist Morphine Derivatives with Emphasis on Medicinal Chemistry.

Relieving severe pains is an unmet medical need, in which opioids are of prime importance and in the focus of pharmaceutical companies. The objective of this study is to characterize the physicochemical properties, namely basicity, lipophilicity and permeability of thirty opioid ligands, which include eleven newly synthesized compounds. pH-potentiometry and the shake-flask method were used for the characterization of species-specific basicity and lipophilicity.

High-Throughput Drug Stability Assessment via Biomimetic Metalloporphyrin-Catalyzed Reactions Using Laser-Assisted Rapid Evaporative Ionization Mass Spectrometry (LA-REIMS).

Building extensive drug candidate libraries as early in the development pipeline as possible, with high-throughput in vitro absorption, distribution, metabolism, and excretion (ADME) profiling, is crucial for the selection of lead compounds to guide subsequent research and production phases. Traditionally, the analysis of metabolic stability assays heavily relies on high-throughput LC-MS/MS (liquid chromatography tandem mass spectrometry) techniques to meet with the lead profiling demands. Laser-assisted rapid evaporative ionization mass spectrometry (LA-REIMS) is a quick and efficient technique for characterizing complex biological samples without laborious sample preparation.

RETINOBLASTOMA-RELATED Has Both Canonical and Noncanonical Regulatory Functions During Thermo-Morphogenic Responses in Arabidopsis Seedlings.

Warm temperatures accelerate plant growth, but the underlying molecular mechanism is not fully understood. Here, we show that increasing the temperature from 22°C to 28°C rapidly activates proliferation in the apical shoot and root meristems of wild-type Arabidopsis seedlings. We found that one of the central regulators of cell proliferation, the cell cycle inhibitor RETINOBLASTOMA-RELATED (RBR), is suppressed by warm temperatures.

Mapping protein binding sites by photoreactive fragment pharmacophores.

Fragment screening is a popular strategy of generating viable chemical starting points especially for challenging targets. Although fragments provide a better coverage of chemical space and they have typically higher chance of binding, their weak affinity necessitates highly sensitive biophysical assays. Here, we introduce a screening concept that combines evolutionary optimized fragment pharmacophores with the use of a photoaffinity handle that enables high hit rates by LC-MS-based detection.

The roles of phosphorylation of signaling proteins in the prognosis of acute myeloid leukemia.

Signaling pathways of Retinoblastoma (Rb) protein, Akt-kinase, and Erk-kinase (extracellular signal-regulated kinase) have an important role in the pathogenesis of acute myeloid leukemia. Constitutive activation of these proteins by phosphorylation contributes to cell survival by regulation of cell cycle, proliferation and proapoptotic signaling processes. According to previous data phosphorylated forms of these proteins represent a worse outcome for cancer patients.

Metabolomic pattern associated with physical sequelae in patients presenting with respiratory symptoms validates the aestivation concept in dehydrated patients.

Hypertonic dehydration is associated with muscle wasting and synthesis of organic osmolytes. We recently showed a metabolic shift to amino acid production and urea cycle activation in coronavirus-2019 (COVID-19), consistent with the aestivation response. The aim of the present investigation was to validate the metabolic shift and development of long-term physical outcomes in the non-COVID cohort of the Biobanque Québécoise de la COVID-19 (BQC19).

Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure.

Background: Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential.

Objectives: The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment.

Methods: DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks.

Beyond the Meso/Macroporous Boundary: Extending Capillary Condensation-Based Pore Size Characterization in Thin Films Through Tailored Adsorptives.

The characterization of thin films containing nanopores with diameters exceeding 50 nm poses significant challenges, especially when deploying sorption-based techniques. Conventional volumetric physisorption or mercury intrusion methods have limited applicability in thin films due to constraints in sample preparation and nondestructive testing. In this context, ellipsometric porosimetry represents a viable alternative, leveraging its optical sensitivity to thin films.

Generation, Transfer, and Loss of Alternative Oxidase Paralogues in the Family.

Alternative oxidase (Aox) is a terminal oxidase operating in branched electron transport. The activity correlates positively with overflow metabolisms in certain , converting intracellular glucose by the shortest possible path into organic acids, like citrate or itaconate. Aox is nearly ubiquitous in fungi, but gene multiplicity is rare.

Expression and purification of the receptor-binding domain of SARS-CoV-2 spike protein in mammalian cells for immunological assays.

The receptor-binding domain (RBD) of the spike glycoprotein of SARS-CoV-2 virus mediates the interaction with the host cell and is required for virus internalization. It is, therefore, the primary target of neutralizing antibodies. The receptor-binding domain soon became the major target for COVID-19 research and the development of diagnostic tools and new-generation vaccines.

Manganese(II) ions suppress the transcription of the citrate exporter encoding gene in .

is an important filamentous fungus used for the industrial production of citric acid. One of the most important factors that affect citric acid production is the concentration of manganese(II) ions present in the culture broth. Under manganese(II)-limiting conditions, the fungus develops a pellet-like morphology that is crucial for high citric acid accumulation.

Circular Business Model for Digital Health Solutions: Protocol for a Scoping Review.

Background: The circular economy reshapes the linear "take, make, and dispose" approach and evolves around minimizing waste and recapturing resources in a closed-loop system. The health sector accounts for 4.6% of global greenhouse gas emissions and has, over the decades, been built to rely on single-use devices and deal with high volumes of medical waste.

Treatment of In-stent Restenosis of the Internal Carotid Artery Using Drug-eluting Balloons.

Purpose: In-stent restenosis (ISR) following internal carotid artery (ICA) stenting is relatively common with an estimated incidence of 5%. Treatment options include repeat angioplasty with conventional or drug-eluting balloons (DEB), repeat stent angioplasty and surgical intervention. Application of DEB in ISR of the coronary and peripheral arteries is an established method; however, data on DEB treatment of ICA ISR are sparse.

Strategies for giving feedback in the operating room.

Feedback is crucial to learning and is a difficult concept to define, occurring as a consequence of learner performance with the ultimate aim of influencing change in the learner. Here, we discuss strategies for giving feedback in the operating room revolving around the following themes: encouraging a sociocultural process, forming an educational alliance, sharing training goals, finding the appropriate time, giving task-specific feedback, approaching unsatisfactory performance and providing follow-up. It is essential that surgeons understand the fundamental feedback theories at play in the operating room described in this article and how they influence surgical training at all stages.

Restoration of Motor Function through Delayed Intraspinal Delivery of Human IL-10-Encoding Nucleoside-Modified mRNA after Spinal Cord Injury.

Efficient in vivo delivery of anti-inflammatory proteins to modulate the microenvironment of an injured spinal cord and promote neuroprotection and functional recovery is a great challenge. Nucleoside-modified messenger RNA (mRNA) has become a promising new modality that can be utilized for the safe and efficient delivery of therapeutic proteins. Here, we used lipid nanoparticle (LNP)-encapsulated human interleukin-10 (hIL-10)-encoding nucleoside-modified mRNA to induce neuroprotection and functional recovery following rat spinal cord contusion injury.

Development of a Laser Microdissection-Coupled Quantitative Shotgun Lipidomic Method to Uncover Spatial Heterogeneity.

Lipid metabolic disturbances are associated with several diseases, such as type 2 diabetes or malignancy. In the last two decades, high-performance mass spectrometry-based lipidomics has emerged as a valuable tool in various fields of biology. However, the evaluation of macroscopic tissue homogenates leaves often undiscovered the differences arising from micron-scale heterogeneity.

Molecular Background of Toxic-Substances-Induced Morphological Alterations in the Umbilical Cord Vessels and Fetal Red Blood Cells.

The relationship between smoking and human health has been investigated mostly in adults, despite the fact that the chemicals originating from sustained maternal smoking disrupt the carefully orchestrated regulatory cascades in the developing fetus. In this study, we followed molecular alterations in the umbilical cord (UC) vessels and fetal red blood cells (RBCs), which faithfully reflect the in vivo status of the fetus. We showed evidence for the decreased level of DNA-PKcs-positive nuclei in samples with smoking origin, which is associated with the impaired DNA repair system.

Harmonization of Rapid Evaporative Ionization Mass Spectrometry Workflows across Four Sites and Testing Using Reference Material and Local Food-Grade Meats.

Rapid evaporative ionization mass spectrometry (REIMS) is a direct tissue metabolic profiling technique used to accurately classify tissues using pre-built mass spectral databases. The reproducibility of the analytical equipment, methodology and tissue classification algorithms has yet to be evaluated over multiple sites, which is an essential step for developing this technique for future clinical applications. In this study, we harmonized REIMS methodology using single-source reference material across four sites with identical equipment: Imperial College London (UK); Waters Research Centre (Hungary); Maastricht University (The Netherlands); and Queen's University (Canada).

Intermuscular adipose tissue in patients with systemic lupus erythematosus.

Objective: Patients with SLE frequently have debilitating fatigue and reduced physical activity. Intermuscular adipose tissue (IMAT) accumulation is associated with reduced physical exercise capacity. We hypothesised that IMAT is increased in patients with SLE and associated with increased fatigue, reduced physical activity and increased inflammation.

Dehydration is associated with production of organic osmolytes and predicts physical long-term symptoms after COVID-19: a multicenter cohort study.

Background: We have previously shown that iatrogenic dehydration is associated with a shift to organic osmolyte production in the general ICU population. The aim of the present investigation was to determine the validity of the physiological response to dehydration known as aestivation and its relevance for long-term disease outcome in COVID-19.

Methods: The study includes 374 COVID-19 patients from the Pronmed cohort admitted to the ICU at Uppsala University Hospital.

Oxidative physiology is weakly associated with pigmentation in birds.

The mechanistic link between avian oxidative physiology and plumage coloration has attracted considerable attention in past decades. Hence, multiple proximal hypotheses were proposed to explain how oxidative state might covary with the production of melanin and carotenoid pigments. Some hypotheses underscore that these pigments (or their precursors, e.