Advances in the structural understanding of opioid allostery.

Activation of the μ opioid receptor (MOR) can give analgesia, but also has dangerous side effects. Drugs that target MOR through an allosteric site, meaning they bind outside of the usual pocket, present a novel mode of receptor activation with different pharmacology relative to orthosteric drugs. Recent structural studies give valuable new information on how allosteric modulators interact with MOR.

New Graphs at the braingraph.org Website for Studying the Aging Brain Circuitry.

Human braingraphs or connectomes are widely studied in the last decade to understand the structural and functional properties of our brain. In the last several years our research group has computed and deposited thousands of human braingraphs to the braingraph.org site, by applying public structural (diffusion) MRI data from young and healthy subjects.

Exercise Types: Physical Activity Mitigates Cardiac Aging and Enhances Mitochondrial Function via PKG-STAT3-Opa1 Axis.

Although age-related deterioration of the cardiac function is a well-studied area of research, the interventions and their molecular pathways have not yet been fully identified. Since physical activity is a powerful preventive measure against cardiac aging, our study compared the effects of long-term voluntary and forced physical activity with a sedentary group, utilizing an aging rat model characterized by mitochondrial dysfunction that contributes to age-related cardiovascular diseases. Four experimental groups were created: (I) young controls (12-week-old); (II) 18-month-old aged sedentary rats; (III) aged group with free access to running wheels for 6 months; (IV) aged rats subjected to forced physical activity for 6 months.

Heterogeneity in oligodendrocyte precursor cell proliferation is dynamic and driven by passive bioelectrical properties.

Oligodendrocyte precursor cells (OPCs) generate myelinating oligodendrocytes and are the main proliferative cells in the adult central nervous system. OPCs are a heterogeneous population, with proliferation and differentiation capacity varying with brain region and age. We demonstrate that during early postnatal maturation, cortical, but not callosal, OPCs begin to show altered passive bioelectrical properties, particularly increased inward potassium (K) conductance, which correlates with G1 cell cycle stage and affects their proliferation potential.

From Nature to Treatment: The Impact of Pterostilbene on Mitigating Retinal Ischemia-Reperfusion Damage by Reducing Oxidative Stress, Inflammation, and Apoptosis.

Retinal ischemia-reperfusion (I/R) injury is a critical pathogenic mechanism in various eye diseases, and an effective therapeutic strategy remains unresolved. Natural derivatives have recently reemerged; therefore, in our present study, we examined the potential therapeutic effects of a stilbenoid that is chemically related to resveratrol. Pterostilbene, recognized for its anti-inflammatory, anti-carcinogenic, anti-diabetic, and neuroprotective properties, counteracts oxidative stress during I/R injury through various mechanisms.

Three classes of propofol binding sites on GABA receptors.

Propofol is a widely used anesthetic and sedative that acts as a positive allosteric modulator of gamma-aminobutyric acid type A (GABA) receptors. Several potential propofol binding sites that may mediate this effect have been identified using propofol-analogue photoaffinity labeling. Ortho-propofol diazirine (o-PD) labels β-H267, a pore-lining residue, whereas AziPm labels residues β-M286, β-M227, and α-I239 in the two membrane-facing interfaces [β(+)/α(-) and α(+)/β(-)] between α and β subunits.

Signaling Modulation Mediated by Ligand Water Interactions with the Sodium Site at μOR.

The mu opioid receptor (μOR) is a target for clinically used analgesics. However, adverse effects, such as respiratory depression and physical dependence, necessitate the development of alternative treatments. Recently we reported a novel strategy to design functionally selective opioids by targeting the sodium binding allosteric site in μOR with a supraspinally active analgesic named .

Structure-Guided Design of Partial Agonists at an Opioid Receptor.

The persistence of chronic pain and continuing overdose deaths from pain-relieving opioids targeting μ opioid receptor (μOR) have fueled the need for reliable long-term analgesics which use different targets and mechanisms. The δ opioid receptor (δOR) is a potential alternative target for non-addictive analgesics to alleviate chronic pain, made more attractive by its lack of respiratory depression associated with μOR agonists. However, early δOR full agonists were found to induce seizures, precluding clinical use.

Opening Amyloid-Windows to the secondary structure of proteins: The amyloidogenecity increases tenfold inside beta-sheets.

Methods from artificial intelligence (AI), in general, and machine learning, in particular, have kept conquering new territories in numerous areas of science. Most of the applications of these techniques are restricted to the classification of large data sets, but new scientific knowledge can seldom be inferred from these tools. Here we show that an AI-based amyloidogenecity predictor can strongly differentiate the border- and the internal hexamers of β-pleated sheets when screening all the Protein Data Bank-deposited homology-filtered protein structures.

Effects of voluntary and forced physical exercise on the retinal health of aging Wistar rats.

Aging is accompanied by an increased prevalence of degenerative conditions, including those affecting ocular health, which significantly impact quality of life and increase the burden on healthcare systems. Among these, retinal aging is of particular concern due to its direct link to vision impairment, a leading cause of disability in the elderly. Vision loss in the aging population is associated with heightened risks of cognitive decline, social isolation, and morbidity.

Novel enzymes for biodegradation of polycyclic aromatic hydrocarbons identified by metagenomics and functional analysis in short-term soil microcosm experiments.

Polycyclic aromatic hydrocarbons (PAHs) are highly toxic, carcinogenic substances. On soils contaminated with PAHs, crop cultivation, animal husbandry and even the survival of microflora in the soil are greatly perturbed, depending on the degree of contamination. Most microorganisms cannot tolerate PAH-contaminated soils, however, some microbial strains can adapt to these harsh conditions and survive on contaminated soils.

The Better Operative Outcomes Software Tool (BOOST) Prospective Study: Improving the Quality of Cataract Surgery Outcomes in Low-Resource Settings.

Purpose: Post-operative vision impairment is common among patients who have undergone cataract surgery in low-resource settings, impacting quality of clinical outcomes and patient experience. This prospective, multisite, single-armed, pragmatic validation study aimed to assess whether receiving tailored recommendations via the free Better Operative Outcomes Software Tool (BOOST) app improved surgical outcomes, as quantified by post-operative unaided distance visual acuity (UVA) measured 1-3 days after surgery.

Methods: During the baseline data collection round, surgeons in low and middle-income countries recorded clinical characteristics of 60 consecutive cataract cases in BOOST.

Assessing the Impact of Influenza Vaccination Timing on Experimental Arthritis: Effects on Disease Progression and Inflammatory Biomarkers.

Numerous studies have indicated a link between vaccines and the exacerbation of autoimmune diseases including rheumatoid arthritis (RA). However, there is no consensus in clinical practice regarding the optimal timing of immunization. Therefore, this study aimed to investigate the impact of the 3Fluart influenza vaccine on the complete Freund's adjuvant (CFA)-induced chronic arthritis rat model and to identify new biomarkers with clinical utility.

Electroretinographical Analysis of the Effect of BGP-15 in Eyedrops for Compensating Global Ischemia-Reperfusion in the Eyes of Sprague Dawley Rats.

Retinal vascular diseases and consequential metabolic disturbances in the eye are major concerns for healthcare systems all around the world. BGP-15, a drug candidate small-molecule [O-(3-piperidino-2-hydroxy-1-propyl) nicotinic amidoxime dihydrochloride], has been formerly demonstrated by our workgroup to be retinoprotective both in the short and long term. Based on these results, the present study was performed to investigate the efficacy of BGP in an eyedrop formulation containing sulfobutylether-β-cyclodextrin (SBECD), which is a solubility enhancer as well.

Quality of Refractive Error Care in Cambodia: An Unannounced Standardized Patient Study.

Purpose: Quality-of-care in refractive error services is essential, as it directly affects vision outcomes, wellbeing, educational attainment, and workforce participation. In Cambodia, uncorrected refractive error is a leading cause of mild and moderate vision impairment in adults. We evaluated the quality of refractive error care in Cambodia by estimating the proportion of prescribed and dispensed spectacles appropriate for people's refractive error needs and factors associated with spectacle quality.

Discovery of Novel Steroid-Based Histamine H Receptor Antagonists/Inverse Agonists.

Steroid-based histamine H receptor antagonists (d-homoazasteroids) were designed by combining distinct structural elements of HTS hit molecules. They were characterized, and several of them displayed remarkably high affinity for H receptors with antagonist/inverse agonist features. Especially, the 17a-aza-d-homolactam chemotype demonstrated excellent HR activity together with significant in vivo H antagonism.

Discovery and biocatalytic characterization of opine dehydrogenases by metagenome mining.

Enzymatic processes play an increasing role in synthetic organic chemistry which requires the access to a broad and diverse set of enzymes. Metagenome mining is a valuable and efficient way to discover novel enzymes with unique properties for biotechnological applications. Here, we report the discovery and biocatalytic characterization of six novel metagenomic opine dehydrogenases from a hot spring environment (mODHs) (EC 1.

Conversion of the CG specific M.MpeI DNA methyltransferase into an enzyme predominantly methylating CCA and CCC sites.

We used structure guided mutagenesis and directed enzyme evolution to alter the specificity of the CG specific bacterial DNA (cytosine-5) methyltransferase M.MpeI. Methylation specificity of the M.

Using Appetitive Motivation to Train Mice for Spatial Learning in the Barnes Maze.

The Barnes maze, a well-known spatial-learning paradigm, is based on the innate fear of rodents of large open spaces and their drive to hide. However, additional aversive stimuli (strong light and threatening sounds) are often necessary to provoke the hiding response while rendering the method cumbersome and more stressful. Our objective was to establish a Barnes maze-learning paradigm in mice using palatable food as a reward.

Reusable Glucose-Based Crown Ethers Anchored to PVC.

The recovery and reuse of the enantioselective catalysts produced by tedious work are important not only from the perspective of green chemistry, but also from the point of view of productivity. Some of the carbohydrate-based crown ethers prepared in our research group were able to generate significant asymmetric induction in certain cases. However, they were not recoverable after the synthesis.

Design and structural validation of peptide-drug conjugate ligands of the kappa-opioid receptor.

Despite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single GPCRs remains an unmet challenge. Here, we develop a computational approach for designing conjugates of lariat-shaped macrocyclized peptides and a small molecule opioid ligand. We demonstrate its feasibility by discovering chemical scaffolds for the kappa-opioid receptor (KOR) with desired pharmacological activities.

iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer.

Microglia are specialized brain-resident macrophages that arise from primitive macrophages colonizing the embryonic brain. Microglia contribute to multiple aspects of brain development, but their precise roles in the early human brain remain poorly understood owing to limited access to relevant tissues. The generation of brain organoids from human induced pluripotent stem cells recapitulates some key features of human embryonic brain development.

Quality of refractive error care in Pakistan: an unannounced standardised patient study.

Objective: Undercorrected refractive errors are the primary cause of vision impairment worldwide, including in Pakistan. However, limited data exist on the quality of refractive error care. Our study assessed the quality of refractive error care in Punjab, Pakistan by estimating the proportion of spectacles that were optimally prescribed.