Non-rodent Models of Atherosclerosis: Repurposing of Existing Drugs and Search for Novel Treatment Strategies.

Atherosclerosis and associated cardiovascular diseases are the leading causes of illness and mortality worldwide. The development of atherosclerosis is a complex process involving oxidative stress, surplus lipid deposition and retention, endothelial dysfunction, and chronic inflammation. Developing novel anti-atherogenic and repurposing existing drugs requires the use of suitable animal models to characterise the fundamental mechanisms underlying atherosclerosis initiation and progression and to evaluate potential therapeutic effects. Commonly used rodent models, however, are not always appropriate, and other models may be required to translate these discoveries into valuable preventive and treatment agents for human applications. Recent advances in gene-editing tools for large animals have allowed the creation of animals that develop atherosclerosis faster and more similarly to humans in terms of lesion localisation and histopathology. In this review, we discuss the major advantages and drawbacks of the main non-rodent animal models of atherosclerosis, particularly rabbits, pigs, zebrafish, and non-human primates. Moreover, we review the application of recently invented novel therapeutic methods and agents, and repurposed existing drugs (such as antidiabetic and anticancer) for atherosclerosis treatment, the efficacy of which is verified on non-rodent animal models of atherosclerosis. In total, the proper selection of a suitable animal model of atherosclerosis facilitates reproducible and rigorous translational research in repurposing of existing drugs, discovering new therapeutic strategies, and validating novel anti-atherosclerotic drugs.

Enhancing Hybrid Photovoltaic-Thermal System Efficiency with Boron Dipyrromethene Dyes.

A library of boron dipyrromethene (BODIPY) compounds was studied to assess their efficacy as components of a working liquid in hybrid photovoltaic-thermal (PVT) systems. Two series of BODIPY dyes were investigated: series I included alkylBODIPYs with varying substitution patterns, while series II included 1,3,5,7-tetramethyl-substituted BODIPYs featuring electron-rich aromatic groups in the meso position, such as naphthalene, anthracene, and carbazole. Series II dyes were designed to exhibit luminescence downshifting due to enhanced UV absorption (300-400 nm) and excited-state energy transfer, leading to visible-region fluorescence under UV excitation. Samples of PVT liquids based on decalin and containing each individual BODIPY dye were tested on a standard a-Si solar cell to evaluate their impact on solar energy conversion efficiency. The thermal behavior of the working liquid and the cell during the illumination cycle was monitored, alongside the cell's electrical characteristics. Energy conversion pathways and the overall effects of the dyes on the system performance were scrutinized. Results indicated that all BODIPY dyes enhanced both the electrical conversion efficiency (up to 2.41% increase) and thermal energy generation (up to 6.87%) compared to the solvent alone. These findings highlight the potential of BODIPY dyes to significantly improve the performance of PVT systems.

Sociopolitical, clinical, and ethical challenges of sustainable fracture care in Haiti.

INTRODUCTION: In low- and middle-income countries such as Haiti, musculoskeletal injuries are the leading cause of morbidity and mortality. Untreated injuries can contribute to decreased mobility, leading to disability and reduced productivity for individuals. The accessibility of timely fracture care poses a substantial challenge in Haiti, where socioeconomic instability and recent surges in gang violence exacerbate an already strained healthcare infrastructure. This manuscript delves into the intricate barriers to sustainable fracture care in Haiti, shedding light on the sociopolitical landscape and clinical challenges that influence the delivery of orthopedic services. ETHICAL DISCUSSION: The ethical considerations in providing fracture care in Haiti are multifaceted, including classic medical principles, self-preservation in the face of violence, issues of justice in resource and service allocation, and concerns of nonmaleficence in the context of international volunteers. These ethical dilemmas arise from the complex interplay of limited resources, the dangers posed by the current sociopolitical climate, and the involvement of international aid in a vulnerable healthcare system. CONCLUSION: To address the clinical and ethical conflicts of providing fracture care in Haiti, solutions include education and training of Haitian orthopedic surgeons, capacity building of healthcare facilities, and establishing ethical standards for international volunteers. This comprehensive approach is vital for advancing sustainable fracture care in Haiti and other resource-limited settings.

How Useful Is TikTok for Patients Searching for Carpal Tunnel Syndrome-Related Treatment Exercises?

Since orthopedic surgery has been slower to acknowledge the rise of social media for distributing medical information, this study aims to evaluate TikTok videos' quality and educational value in relation to carpal tunnel syndrome treatment exercises. TikTok was searched using the hashtags "#carpaltunnelexercises", "#carpaltunnelremedies", "#carpaltunnelrehab", and "#physicaltherapyforcarpaltunnel". The engagement indicators were documented and the video content quality was assessed using the DISCERN, CTEES, JAMA, and GQS grading scales. There were 101 videos included, which accumulated 20,985,730 views. The videos received 1,460,953 likes, 15,723 comments, 243,245 favorites, and 159,923 shares. Healthcare professionals were responsible for 72% of the video uploads, whereas general users contributed 28%. More healthcare professionals' videos were graded as "poor" (79%) compared to general users (21%). General users received slightly more video grades of "very poor" (52%) than healthcare professionals (48%). For the DISCERN grading, the videos by healthcare professionals were significantly better than those by general users in terms of reliability, achieving aims, and relevancy. They were also superior in the overall composition of the health information derived from the total DISCERN score. However, no significant differences were found between the two groups when using the CTEES, JAMA, and GQS grading scales. Overall, despite the emergence of TikTok as a medical information tool, the quality and educational value of the carpal tunnel syndrome exercise videos were poor.

Cisplatin Resistance and Metabolism: Simplification of Complexity.

Cisplatin is one of the most well-known anti-cancer drugs and has demonstrated efficacy against numerous tumor types for many decades. However, a key challenge with cisplatin, as with any chemotherapeutic agent, is the development of resistance with a resultant loss of efficacy. This resistance is often associated with metabolic alterations that allow insensitive cells to divide and survive under treatment. These adaptations could vary greatly among different tumor types and may seem questionable and incomprehensible at first glance. Here we discuss the disturbances in glucose, lipid, and amino acid metabolism in cisplatin-resistant cells as well as the roles of ferroptosis and autophagy in acquiring this type of drug intolerance.

A Comparison of Two Versions of the CRISPR-Sirius System for the Live-Cell Visualization of the Borders of Topologically Associating Domains.

In recent years, various technologies have emerged for the imaging of chromatin loci in living cells via catalytically inactive Cas9 (dCas9). These technologies facilitate a deeper understanding of the mechanisms behind the chromatin dynamics and provide valuable kinetic data that could not have previously been obtained via FISH applied to fixed cells. However, such technologies are relatively complicated, as they involve the expression of several chimeric proteins as well as sgRNAs targeting the visualized loci, a process that entails many technical subtleties. Therefore, the effectiveness in visualizing a specific target locus may be quite low. In this study, we directly compared two versions of a previously published CRISPR-Sirius method based on the use of sgRNAs containing eight MS2 or PP7 stem loops and the expression of MCP or PCP fused to fluorescent proteins. We assessed the visualization efficiency for several unique genomic loci by comparing the two approaches in delivering sgRNA genes (transient transfection and lentiviral transduction), as well as two CRISPR-Sirius versions (with PCP and with MCP). The efficiency of visualization varied among the loci, and not all loci could be visualized. However, the MCP-sfGFP version provided more efficient visualization in terms of the number of cells with signals than PCP-sfGFP for all tested loci. We also showed that lentiviral transduction was more efficient in locus imaging than transient transfection for both CRISPR-Sirius systems. Most of the target loci in our study were located at the borders of topologically associating domains, and we defined a set of TAD borders that could be effectively visualized using the MCP-sfGFP version of the CRISPR-Sirius system. Altogether, our study validates the use of the CRISPR-Sirius technology for live-cell visualization and highlights various technical details that should be considered when using this method.

Green-light Hydrosilylation Photocatalysis with Platinum(II) Metalla-N-Heterocyclic Carbene Complexes.

Platinum(II) metalla-N-heterocyclic carbene complexes featuring pyridyl heterocyclic moiety demonstrate remarkable catalytic efficiency in alkyne hydrosilylation under green light irradiation. The photocatalytic properties of complexes are rationalised by the photo-induced charge transfer occurring in extended condensed system identified with the help of various experimental (UV/vis and emission spectroscopy, cyclic voltammetry) and theoretical methods (DFT/TD-DFT, IFCT analysis).

Difluoroboron complexes as versatile precursors for steroid modification. Lumiestrone-based steroid derivatives: synthesis and structural studies.

A preparation method for steroid-based difluoroboron complexes has been developed using lumiestrone as a steroid example. Previously inaccessible lumiestrone-based difluoroboron complexes annulated at positions 16 and 17 of the D ring have been prepared. Such difluoroboron complexes may have large synthetic potential for heterofunctionalization of steroids at the D ring. An application of a borylation mixture Ac2O-BF3•OEt2 significantly simplify the preparation of steroid "dimers" bearing two estrone moieties connected at positions 2 and 2' via a linker. Crystal structures of key representatives have been determined by X­ray diffraction.

Polarization-dependent gain in bismuth-doped phospho- and germanosilicate fiber amplifiers.

Polarization-dependent gain (PDG) effect was studied in a conventional core-pumping configuration of bismuth-doped fiber amplifiers (BDFAs) based on PANDA-type phospho- and germanosilicate core fibers. The PDG value was determined as the gain difference between the orthogonal signal polarizations, which was found to be in range of 2.5-3 dB at total gain of >20 dB in such BDFAs. This effect is more pronounced for BDFA with a germanosilicate fiber. The experimental results are in a good agreement with the calculated data derived from the simulation model, relying on the anisotropy parameter of bismuth active centers (BACs) obtained from the degree of luminescence polarization, which ranges between 9 and 12% for BACs-Si and 18 and 22% for BACs-P. The obtained data can be useful for the optimization of performance of BDFAs and studying structural peculiarities of BACs.

Second Order Dynamics Featuring Tikhonov Regularization and Time Scaling.

In a Hilbert setting we aim to study a second order in time differential equation, combining viscous and Hessian-driven damping, containing a time scaling parameter function and a Tikhonov regularization term. The dynamical system is related to the problem of minimization of a nonsmooth convex function. In the formulation of the problem as well as in our analysis we use the Moreau envelope of the objective function and its gradient and heavily rely on their properties. We show that there is a setting where the newly introduced system preserves and even improves the well-known fast convergence properties of the function and Moreau envelope along the trajectories and also of the gradient of Moreau envelope due to the presence of time scaling. Moreover, in a different setting we prove strong convergence of the trajectories to the element of minimal norm from the set of all minimizers of the objective. The manuscript concludes with various numerical results.

Analytical Methods for Assessing Thiol Antioxidants in Biological Fluids: A Review.

Redox metabolism is an integral part of the glutathione system, encompassing reduced and oxidized glutathione, hydrogen peroxide, and associated enzymes. This core process orchestrates a network of thiol antioxidants like thioredoxins and peroxiredoxins, alongside critical thiol-containing proteins such as mercaptoalbumin. Modifications to thiol-containing proteins, including oxidation and glutathionylation, regulate cellular signaling influencing gene activities in inflammation and carcinogenesis. Analyzing thiol antioxidants, especially glutathione, in biological fluids offers insights into pathological conditions. This review discusses the analytical methods for biothiol determination, mainly in blood plasma. The study includes all key methodological aspects of spectroscopy, chromatography, electrochemistry, and mass spectrometry, highlighting their principles, benefits, limitations, and recent advancements that were not included in previously published reviews. Sample preparation and factors affecting thiol antioxidant measurements are discussed. The review reveals that the choice of analytical procedures should be based on the specific requirements of the research. Spectrophotometric methods are simple and cost-effective but may need more specificity. Chromatographic techniques have excellent separation capabilities but require longer analysis times. Electrochemical methods enable real-time monitoring but have disadvantages such as interference. Mass spectrometry-based approaches have high sensitivity and selectivity but require sophisticated instrumentation. Combining multiple techniques can provide comprehensive information on thiol antioxidant levels in biological fluids, enabling clearer insights into their roles in health and disease. This review covers the time span from 2010 to mid-2024, and the data were obtained from the SciFinder® (ACS), Google Scholar (Google), PubMed®, and ScienceDirect (Scopus) databases through a combination search approach using keywords.

Synthesis, electrochemical properties, and antioxidant activity of sterically hindered catechols with 1,3,4-oxadiazole, 1,2,4-triazole, thiazole or pyridine fragments.

A series of new RS-, RS-CH2- and R2N-CH2-functionalized сatechols with heterocyclic fragments such as 1,3,4-oxadiazole, 1,2,4-triazole, thiazole, or pyridine were synthesized by the reaction of 3,5-di-tert-butyl-o-benzoquinone or 3,5-di-tert-butyl-6-methoxymethylcatechol with different heterocyclic thiols. The S-functionalized catechols were prepared by the Michael reaction from 3,5-di-tert-butyl-o-benzoquinone and the corresponding thiols. The starting reagents such as substituted 1,3,4-oxadiazole-2-thiols and 4H-triazole-3-thiols are characterized by thiol-thione tautomerism, therefore their reactions with 3,5-di-tert-butyl-6-methoxymethylcatechol can proceed at the sulfur or nitrogen atom. In the case of mercapto-derivatives of thiazole or pyridine, this process leads to the formation of the corresponding thioethers with a methylene linker. At the same time, thiolated 1,3,4-oxadiazole or 1,2,4-triazole undergo alkylation at the nitrogen atom in the reaction with 3,5-di-tert-butyl-6-methoxymethylcatechol to form the corresponding thiones. The yield of reaction products ranges from 42 to 80%. The crystal structures of catechols with 3-nitropyridine or 1,3,4-oxadiazole-2(3H)-thione moieties were established by single-crystal X-ray analysis. The possibility of forming intra- and intermolecular hydrogen bonds has been established for these compounds. The electrochemical behavior of the studied compounds is influenced by several factors: the nature of the heterocycle and its substituents, the presence of a sulfur atom in the catechol ring, or a thione group in the heterocyclic core. The radical scavenging activity and antioxidant properties were determined using the reaction with synthetic radicals, the cupric reducing antioxidant capacity assay, the inhibition process of superoxide radical anion formation by xanthine oxidase, and the process of lipid peroxidation of rat liver (Wistar) homogenates in vitro.

Development of an Intranasal In Situ System for Ribavirin Delivery: In Vitro and In Vivo Evaluation.

Recently, ribavirin has demonstrated effectiveness in treating glioblastoma through intranasal administration utilizing the nose-to-brain delivery route. Enhancing ribavirin's bioavailability can be achieved by utilizing intranasal stimuli-responsive systems that create a gel on the nasal mucosa. The research examined thermosensitive, pH-sensitive, and ion-selective polymers in various combinations and concentrations, chosen in line with the current Quality by Design (QbD) approach in pharmaceutical development. Following a thorough assessment of key parameters, the optimal composition of gellan gum at 0.5%, Poloxamer 124 at 2%, and purified water with ribavirin concentration at 100 mg/mL was formulated and subjected to in vivo testing. Through experiments on male rats, the nose-to-brain penetration mechanism of the active pharmaceutical ingredient (API) was elucidated, showcasing drug accumulation in the olfactory bulbs and brain.

Predicting fluorescence to singlet oxygen generation quantum yield ratio for BODIPY dyes using QSPR and machine learning.

Functional dyes that are capable of both bright fluorescence and efficient singlet oxygen generation are crucial for theranostic techniques, which integrate fluorescence imaging and photodynamic therapy (PDT). The development of new functional dyes for theranostics is often costly and time-consuming due to laborious synthesis and post-synthetic screening of large libraries of compounds. In this work, we describe machine learning methods suitable for simultaneous prediction of fluorescence and photosensitizing ability of heavy-atom-free boron dipyrromethene (BODIPY) compounds. We analysed the ratio between fluorescence quantum yield (ΦFl) and singlet oxygen quantum yield (ΦΔ) for over 70 BODIPY structures in polar (acetonitrile) and non-polar (toluene) solvents, which mimic hydrophilic and hydrophobic cell environments, respectively. QSPR models were developed based on more than 5000 calculated molecular descriptors, including quantum chemical and topological descriptors. We applied multiple linear regression (MLR), support vector regression (SVR), and random forest regression (RFR) methods for model building and optimization. The resulting models demonstrated robust statistical parameters (R2 = 0.73-0.91) for both polar and non-polar media. The relative contributions of the descriptors to the models were assessed, identifying Eig03_EA(dm), F01[C-N], and TDB06p as the most influential. These results demonstrate that QSPR machine learning methods are effective in predicting key photochemical parameters of BODIPY photosensitizers, thereby potentially streamlining the development of theranostic agents.

Response of Fluorescent Boron Difluoride ß-Diketonates to X-Rays.

This paper reports the results of a detailed study of the optical response of boron difluoride curcuminoids to radiation exposure. Two lines of the dyes fundamentally different in structure (namely, symmetrical and asymmetrical) were tested. If the absorption responses of their solutions in chloroform to X-rays turns out to be quite close quantitatively (note that it has a very indicative visual manifestation - a gradual discoloration is observed in the dose range up to 300 Gy), the fluorescence ones differ notably: among other things, the former demonstrate much more sensitive reactions (the corresponding limit of detection values ​​differ by up to 2.36-fold). Nevertheless, in both parameters, these dyes generally show good linearity of the response as in classical coordinates (up to ≈ 100-150 Gy), as in semi-logarithmic ones (up to 1000 Gy). Since the main reason for such behavior seems to be the radiation-induced decomposition of the dyes, its possible scheme and corresponding "weak links" in the structure of the molecules (in other words, radiosensitive elements) are proposed for each case. For example, these include N(CH3)2 fragments at the ends of dimethylaminostyryl groups. It is precisely their detachment that determines the observed optical response of asymmetrical dyes. Thus, the results obtained provide some insight into the possibilities of controlling the sensitivity of organic dyes to irradiation by changing their structure.

Second-line drug-resistant TB and associated risk factors in Karakalpakstan, Uzbekistan.

BACKGROUND: Drug-resistant TB (DR-TB) remains a major public health threat. In 2022, Uzbekistan reported 2,117 cases of DR-TB, with 69% tested for fluoroquinolone resistance. Limited information is available on the prevalence of resistance to bedaquiline, linezolid, and fluoroquinolone, which are key components of the all-oral treatment regimen for rifampicin-resistant TB in Uzbekistan. METHODS: A retrospective study was conducted using extensive programmatic data from 2019 to 2023 in Uzbekistan. We assessed second-line drug-resistant TB (SLDR-TB) rates using phenotypic drug susceptibility testing (pDST). Demographic and clinical characteristics associated with SLDR-TB were analysed using multivariable logistic regression models based on the Allen-Cady approach. RESULTS: In total, 2,405 patients with TB who had undergone pDST were included (median age 40 years, 47% female). The overall SLDR-TB resistance rate was 24% (95% CI 22-26). Prevalence of resistance to bedaquiline, linezolid, moxifloxacin, levofloxacin, and amikacin were respectively 3.1%, 0.8%, 15%, 13%, and 12%. Risk factors for SLDR-TB were resistance to rifampicin and/or isoniazid, exposure to clofazimine, retreatment status, contact with drug-susceptible TB case or DR-TB case, and diabetes. CONCLUSIONS: The high prevalence of SLDR-TB is of major concern, emphasising the need for baseline pDST in RR-TB treatment. Identified risk factors can aid early detection of at-risk individuals and inform clinical practice.

CONTEXTE: La TB résistante aux médicaments (DR-TB) reste une menace majeure pour la santé publique. En 2022, l'Ouzbékistan a signalé 2 117 cas de DR-TB, dont 69% ont été testés pour la résistance aux fluoroquinolones. Les informations sur la prévalence de la résistance à la bédaquiline, au linézolide et aux fluoroquinolones, qui sont des composants clés du traitement entièrement oral de la TB résistante à la rifampicine en Ouzbékistan, sont limitées. MÉTHODES: Une étude rétrospective a été menée en utilisant des données programmatiques exhaustives de 2019 à 2023 en Ouzbékistan. Nous avons évalué les taux de TB résistante aux médicaments de deuxième ligne (SLDR-TB, pour l'anglais, « second-line drug-resistant TB ¼) en utilisant des tests de sensibilité phénotypique aux médicaments (pDST). Les caractéristiques démographiques et cliniques associées à la SLDR-TB ont été analysées à l'aide de modèles de régression logistique multivariés basés sur l'approche Allen-Cady. RÉSULTATS: Au total, 2 405 patients atteints de TB ayant subi un pDST ont été inclus (âge médian de 40 ans, 47% de femmes). Le taux global de résistance à la SLDR-TB était de 24% (CI à 95% 22­26). La prévalence de la résistance à la bédaquiline, au linézolide, à la moxifloxacine, à la lévofloxacine et à l'amikacine était respectivement de 3,1%, 0,8%, 15%, 13% et 12%. Les facteurs de risque de SLDR-TB comprenaient la résistance à la rifampicine et/ou à l'isoniazide, l'exposition à la clofazimine, le statut de retraitement, le contact avec un cas de TB sensible aux médicaments ou de DR-TB, et le diabète. CONCLUSIONS: La prévalence élevée de la SLDR-TB est une source de préoccupation majeure, soulignant la nécessité de réaliser des pDST de base dans le traitement de la TB résistante à la rifampicine. Les facteurs de risque identifiés peuvent aider à la détection précoce des individus à risque et à informer la pratique clinique.

Blue Light-Induced Accelerated Formation of Melanolipofuscin-Like Organelles in Japanese Quail RPE Cells: An Electron Microscopic Study.

Purpose: The retinal pigment epithelium (RPE) is a monolayer of epithelial cells essential for photoreceptor function and viability. Quail Coturnix japonica is a convenient experimental animal model for the study of age and pathological retina processes to an accelerated time regime. The three main types of pigment granules present in the RPE are melanin-containing melanosomes, lipofuscin-containing lipofuscin granules, and mixed melanolipofuscin granules containing both melanin and lipofuscin. The purpose of this work was to study the process of melanolipofuscinogenesis during aging and under light exposure. Methods: We examined melanolipofuscin granules in "macular" areas, the area of the retina containing oxycarotenoids, as a function of the macula in humans, of the quail retina by transmission electron microscopy in young, middle-aged, and old birds, and in middle-aged birds irradiated with blue LED light (450 nm, 4 J/cm2). Results: It has been shown that during photo-oxidative stress caused by the action of blue light on the quail eye, active fusion of melanosomes and lipofuscin granules occurs with formation of various types, including giant, mixed melanolipofuscin-like granules. Increased accumulation of melanolipofuscin-like granules was also observed in non-irradiated old birds. Conclusions: It is assumed that the decrease in the number of melanosomes in the RPE during aging and photo-oxidative stress is associated with their fusion with lipofuscin granules and subsequent degradation of melanin by reactive oxygen species formed in melanolipofuscin-like granules. The disappearance of melanin deprives the RPE cells of light-filtering and antioxidant protection, and significantly increases the risk of their oxidative stress.

Cellular Prion Protein Conformational Shift after Liquid-Liquid Phase Separation Regulated by a Polymeric Antagonist and Mutations.

Liquid-liquid phase separation (LLPS) of intrinsically disordered proteins has been associated with neurodegenerative diseases, although direct mechanisms are poorly defined. Here, we report on a maturation process for the cellular prion protein (PrPC) that involves a conformational change after LLPS and is regulated by mutations and poly(4-styrenesulfonic acid-co-maleic acid) (PSCMA), a molecule that has been reported to rescue Alzheimer's disease-related cognitive deficits by antagonizing the interaction between PrPC and amyloid-ß oligomers (Aßo). We show that PSCMA can induce reentrant LLPS of PrPC and lower the saturation concentration (Csat) of PrPC by 100-fold. Regardless of the induction method, PrPC molecules subsequently undergo a maturation process to restrict molecular motion in a more solid-like state. The PSCMA-induced LLPS of PrPC stabilizes the intermediate LLPS conformational state detected by NMR, though the final matured ß-sheet-rich state of PrPC is indistinguishable between induction conditions. The disease-associated E200 K mutation of PrPC also accelerates maturation. This post-LLPS shift in protein conformation and dynamics is a possible mechanism of LLPS-induced neurodegeneration.