Exogenous Iron Induces Mitochondrial Lipid Peroxidation, Lipofuscin Accumulation, and Ferroptosis in H9c2 Cardiomyocytes.

Lipid peroxidation plays an important role in various pathologies and aging, at least partially mediated by ferroptosis. The role of mitochondrial lipid peroxidation during ferroptosis remains poorly understood. We show that supplementation of exogenous iron in the form of ferric ammonium citrate at submillimolar doses induces production of reactive oxygen species (ROS) and lipid peroxidation in mitochondria that precede ferroptosis in H9c2 cardiomyocytes. The mitochondria-targeted antioxidant SkQ1 and the redox mediator methylene blue, which inhibits the production of ROS in complex I of the mitochondrial electron transport chain, prevent both mitochondrial lipid peroxidation and ferroptosis. SkQ1 and methylene blue also prevented accumulation of lipofuscin observed after 24 h incubation of cardiomyocytes with ferric ammonium citrate. Using isolated cardiac mitochondria as an in vitro ferroptosis model, it was shown that rotenone (complex I inhibitor) in the presence of ferrous iron stimulates lipid peroxidation and lipofuscin accumulation. Our data indicate that ROS generated in complex I stimulate mitochondrial lipid peroxidation, lipofuscin accumulation, and ferroptosis induced by exogenous iron.

The Expression of Cell Cycle Cyclins in a Human Megakaryoblast Cell Line Exposed to Simulated Microgravity.

The study of the physiological and pathophysiological processes under extreme conditions facilitates a better understanding of the state of a healthy organism and can also shed light on the pathogenesis of diseases. In recent years, it has become evident that gravitational stress affects both the whole organism and individual cells. We have previously demonstrated that simulated microgravity inhibits proliferation, induces apoptosis, changes morphology, and alters the surface marker expression of megakaryoblast cell line MEG-01. In the present work, we investigate the expression of cell cycle cyclins in MEG-01 cells. We performed several experiments for 24 h, 72 h, 96 h and 168 h. Flow cytometry and Western blot analysis demonstrated that the main change in the levels of cyclins expression occurs under conditions of simulated microgravity after 96 h. Thus, the level of cyclin A expression showed an increase in the RPM group during the first 4 days, followed by a decrease, which, together with the peak of cyclin D, may indicate inhibition of the cell cycle in the G2 phase, before mitosis. In addition, based on the data obtained by PCR analysis, we were also able to see that both cyclin A and cyclin B expression showed a peak at 72 h, followed by a gradual decrease at 96 h. STED microscopy data also confirmed that the main change in cyclin expression of MEG-01 cells occurs at 96 h, under simulated microgravity conditions, compared to static control. These results suggested that the cell cycle disruption induced by RPM-simulated microgravity in MEG-01 cells may be associated with the altered expression of the main regulators of the cell cycle. Thus, these data implicate the development of cellular stress in MEG-01 cells, which may be important for proliferating human cells exposed to microgravity in real space.

Associations between e-cigarette marketing exposure and vaping nicotine and cannabis among U.S. adults, 2021.

INTRODUCTION: Little is known about the influence of e-cigarette marketing on cannabis vaping behaviors. This study examined the associations between e-cigarette marketing exposure and nicotine and cannabis vaping among adults. METHODS: This cross-sectional study included a U.S. nationally representative sample of adults from the Wave 6 survey of the Population Assessment of Tobacco and Health Study. We used multinomial logistic regressions to examine the associations between past 30-day e-cigarette marketing exposure and past 30-day vaping behavior (sole- and dual-vaping of nicotine and cannabis) overall and stratified by age. RESULTS: Overall, 52.0 % of respondents reported e-cigarette marketing exposure, and 89.8 %, 5.6 %, 3.2 %, and 1.4 % reported no vaping, sole-nicotine vaping, sole-cannabis vaping, and dual-vaping, respectively. E-cigarette marketing exposure was associated with increased odds of reporting sole-cannabis vaping versus no vaping (adjusted risk ratio [aRR], 1.31; 95 % confidence interval [CI], 1.09-1.57) and dual-vaping versus no vaping (aRR, 1.26; 95 % CI, 1.01-1.57). This association was found among those aged 18-24 and 25-34 years. It was also associated with increased odds of reporting sole-cannabis vaping versus sole-nicotine vaping (aRR, 1.28; 95 % CI, 1.04-1.58). This association was found among those aged 18-24 years. DISCUSSION: E-cigarette marketing exposure was associated with sole-cannabis vaping and dual-vaping, not sole-nicotine vaping among U.S. adults. Such associations were mainly driven by young adults aged 18-24 and 25-34 years. Greater restrictions on tobacco marketing may have reduced the influence of e-cigarette marketing on nicotine vaping, while gaps in marketing restrictions for cannabis may contribute to e-cigarette marketing influence on cannabis vaping.

Effect of Short-Term Restraint Stress on the Hypothalamic Transcriptome Profiles of Rats with Inherited Stress-Induced Arterial Hypertension (ISIAH) and Normotensive Wistar Albino Glaxo (WAG) Rats.

Emotional stress is one of the health risk factors in the modern human lifestyle. Stress exposure can provoke the manifestation of various pathological conditions, one of which is a sharp increase in the blood pressure level. In the present study, we analyzed changes in the transcriptome profiles of the hypothalamus of hypertensive ISIAH and normotensive WAG rats exposed to a single short-term restraint stress (the rat was placed in a tight wire-mesh cage for 2 h). This type of stress can be considered emotional stress. The functional annotation of differentially expressed genes allowed us to identify the most significantly altered biological processes in the hypothalamus of hypertensive and normotensive rats. The study made it possible to identify a group of genes that describe a general response to stress, independent of the rat genotype, as well as a hypothalamic response to stress specific to each strain. The alternatively changing expression of the Npas4 (neuronal PAS domain protein 4) gene, which is downregulated in the hypothalamus of the control WAG rats and induced in the hypothalamus of hypertensive ISIAH rats, is suggested to be the key event for understanding inter-strain differences in the hypothalamic response to stress. The stress-dependent ISIAH strain-specific induction of Fos and Jun gene transcription may play a crucial role in neuronal activation in this rat strain. The data obtained can be potentially useful in the selection of molecular targets for the development of pharmacological approaches to the correction of stress-induced pathologies related to neuronal excitability, taking into account the hypertensive status of the patients.

In Search for Low-Molecular-Weight Ligands of Human Serum Albumin That Affect Its Affinity for Monomeric Amyloid ß Peptide.

An imbalance between production and excretion of amyloid ß peptide (Aß) in the brain tissues of Alzheimer's disease (AD) patients leads to Aß accumulation and the formation of noxious Aß oligomers/plaques. A promising approach to AD prevention is the reduction of free Aß levels by directed enhancement of Aß binding to its natural depot, human serum albumin (HSA). We previously demonstrated the ability of specific low-molecular-weight ligands (LMWLs) in HSA to improve its affinity for Aß. Here we develop this approach through a bioinformatic search for the clinically approved AD-related LMWLs in HSA, followed by classification of the candidates according to the predicted location of their binding sites on the HSA surface, ranking of the candidates, and selective experimental validation of their impact on HSA affinity for Aß. The top 100 candidate LMWLs were classified into five clusters. The specific representatives of the different clusters exhibit dramatically different behavior, with 3- to 13-fold changes in equilibrium dissociation constants for the HSA-Aß40 interaction: prednisone favors HSA-Aß interaction, mefenamic acid shows the opposite effect, and levothyroxine exhibits bidirectional effects. Overall, the LMWLs in HSA chosen here provide a basis for drug repurposing for AD prevention, and for the search of medications promoting AD progression.

A PD-1highCD4+ T Cell Population With a Cytotoxic Phenotype is Associated With Interstitial Lung Disease in Systemic Sclerosis.

OBJECTIVE: T cells contribute to tissue injury in systemic sclerosis (SSc), yet the specific T cell subsets expanded in patients with SSc remain incompletely defined. Here we evaluated specific phenotypes and functions of peripheral helper T (Tph) and follicular helper T (Tfh) cells, which have been implicated in autoantibody production, and assessed their associations with clinical features in a well-characterized cohort of patients with SSc. METHODS: Mass cytometry of T cells from peripheral blood mononuclear cells of patients with SSc and controls were evaluated using t-distributed stochastic neighbor embedding visualization, biaxial gating, and marker expression levels. Findings were validated with flow cytometry and in vitro assays. RESULTS: The frequencies of PD-1highCXCR5+ Tfh cells and PD-1highCXCR5- Tph cells were similar in patients with SSc and controls. t-distributed stochastic neighbor embedding visualization (tSNE) revealed distinct populations within the PD-1highCXCR5- cells distinguished by expression of HLA-DR and inducible costimulator (ICOS). Among PD-1highCXCR5- cells, only the HLA-DR+ICOS- cell population was expanded in patients with SSc. Cytometric and RNA sequencing analyses indicated that these cells expressed cytotoxic rather than B cell helper features. HLA-DR+ICOS- PD-1highCXCR5- cells were less potent in inducing B cell plasmablast differentiation and antibody production than comparator T helper cell populations. HLA-DR+ICOS-PD-1highCXCR5- cells were significantly associated with the presence and severity of interstitial lung disease among patients with SSc. CONCLUSION: Among PD-1highCXCR5- T cells, a subset of HLA-DR+ICOS- cells with cytotoxic features is specifically expanded in patients with SSc and is significantly associated with interstitial lung disease severity. This potential cytotoxicity appearing in the CD4 T cell population can be evaluated as a prognostic disease biomarker in patients with SSc.

Sliding Window INteraction Grammar (SWING): a generalized interaction language model for peptide and protein interactions.

The explosion of sequence data has allowed the rapid growth of protein language models (pLMs). pLMs have now been employed in many frameworks including variant-effect and peptide-specificity prediction. Traditionally, for protein-protein or peptide-protein interactions (PPIs), corresponding sequences are either co-embedded followed by post-hoc integration or the sequences are concatenated prior to embedding. Interestingly, no method utilizes a language representation of the interaction itself. We developed an interaction LM (iLM), which uses a novel language to represent interactions between protein/peptide sequences. Sliding Window Interaction Grammar (SWING) leverages differences in amino acid properties to generate an interaction vocabulary. This vocabulary is the input into a LM followed by a supervised prediction step where the LM's representations are used as features. SWING was first applied to predicting peptide:MHC (pMHC) interactions. SWING was not only successful at generating Class I and Class II models that have comparable prediction to state-of-the-art approaches, but the unique Mixed Class model was also successful at jointly predicting both classes. Further, the SWING model trained only on Class I alleles was predictive for Class II, a complex prediction task not attempted by any existing approach. For de novo data, using only Class I or Class II data, SWING also accurately predicted Class II pMHC interactions in murine models of SLE (MRL/lpr model) and T1D (NOD model), that were validated experimentally. To further evaluate SWING's generalizability, we tested its ability to predict the disruption of specific protein-protein interactions by missense mutations. Although modern methods like AlphaMissense and ESM1b can predict interfaces and variant effects/pathogenicity per mutation, they are unable to predict interaction-specific disruptions. SWING was successful at accurately predicting the impact of both Mendelian mutations and population variants on PPIs. This is the first generalizable approach that can accurately predict interaction-specific disruptions by missense mutations with only sequence information. Overall, SWING is a first-in-class generalizable zero-shot iLM that learns the language of PPIs.

Nature-Inspired 1-Phenylpyrrolo[2,1-a]isoquinoline Scaffold for Novel Antiproliferative Agents Circumventing P-Glycoprotein-Dependent Multidrug Resistance.

Previous studies have shown that some lamellarin-resembling annelated azaheterocyclic carbaldehydes and related imino adducts, sharing the 1-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (1-Ph-DHPIQ) scaffold, are cytotoxic in some tumor cells and may reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). Herein, several novel substituted 1-Ph-DHPIQ derivatives were synthesized which carry carboxylate groups (COOH, COOEt), nitrile (CN) and Mannich bases (namely, morpholinomethyl derivatives) in the C2 position, as replacements of the already reported aldehyde group. They were evaluated for antiproliferative activity in four tumor cell lines (RD, HCT116, HeLa, A549) and for the ability of selectively inhibiting P-gp-mediated MDR. Lipophilicity descriptors and molecular docking calculations helped us in rationalizing the structure-activity relationships in the P-gp inhibition potency of the investigated 1-Ph-DHPIQs. As a main outcome, a morpholinomethyl Mannich base (8c) was disclosed which proved to be cytotoxic to all the tested tumor cell lines in the low micromolar range (IC50 < 20 µM) and to inhibit in vitro the efflux pumps P-gp and MRP1 responsible for MDR, with IC50s of 0.45 and 12.1 µM, respectively.

Evaluating Suicide Risk Stratification in Outpatient Settings: A Vignette-Based Approach.

Suicide risk assessment and stratification are a key suicide prevention strategy in mental health care systems that treat military service members and veterans. The aim of the current mixed-method project was to address a gap in our knowledge as to how therapists make these important clinical decisions. This manuscript reports the results of a project during which six vignettes were developed reflecting varying levels of risk according to the Rocky Mountain MIRECC Risk Stratification Table. Mental health therapists were asked to evaluate the risk level of each vignette, determine a treatment disposition, and provide justification for their ratings. The results of the study indicate that therapists can reliably evaluate risk, but that treatment planning tended to be based more on vignette-specific factors than essential features of the risk model. The qualitative findings revealed variations in the definition and perception of foundational concepts, suggesting a need for further research and training in these domains. Overall, the results support the use of vignettes as a method to assess clinical decision-making and provide several areas for further training and research.

Recognition of granulocyte-macrophage colony-stimulating factor by specific S100 proteins.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic myelopoietic growth factor and proinflammatory cytokine, clinically used for multiple indications and serving as a promising target for treatment of many disorders, including cancer, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, COVID-19. We have previously shown that dimeric Ca2+-bound forms of S100A6 and S100P proteins, members of the multifunctional S100 protein family, are specific to GM-CSF. To probe selectivity of these interactions, the affinity of recombinant human GM-CSF to dimeric Ca2+-loaded forms of 18 recombinant human S100 proteins was studied by surface plasmon resonance spectroscopy. Of them, only S100A4 protein specifically binds to GM-CSF with equilibrium dissociation constant, Kd, values of 0.3-2 µM, as confirmed by intrinsic fluorescence and chemical crosslinking data. Calcium removal prevents S100A4 binding to GM-CSF, whereas monomerization of S100A4/A6/P proteins disrupts S100A4/A6 interaction with GM-CSF and induces a slight decrease in S100P affinity for GM-CSF. Structural modelling indicates the presence in the GM-CSF molecule of a conserved S100A4/A6/P-binding site, consisting of the residues from its termini, helices I and III, some of which are involved in the interaction with GM-CSF receptors. The predicted involvement of the 'hinge' region and F89 residue of S100P in GM-CSF recognition was confirmed by mutagenesis. Examination of S100A4/A6/P ability to affect GM-CSF signaling showed that S100A4/A6 inhibit GM-CSF-induced suppression of viability of monocytic THP-1 cells. The ability of the S100 proteins to modulate GM-CSF activity is relevant to progression of various neoplasms and other diseases, according to bioinformatics analysis. The direct regulation of GM-CSF signaling by extracellular forms of the S100 proteins should be taken into account in the clinical use of GM-CSF and development of the therapeutic interventions targeting GM-CSF or its receptors.

Synthesis of Triphenylphosphonium-Linked Derivative of 3,5-Ditert-butyl-4-hydroxybenzylidene-malononitrile (SF6847) via Knoevenagel Reaction Yields an Effective Mitochondria-Targeted Protonophoric Uncoupler.

Mitochondrial uncouplers are actively sought as potential therapeutics. Here, we report the first successful synthesis of mitochondria-targeted derivatives of the highly potent uncoupler 3,5-ditert-butyl-4-hydroxybenzylidene-malononitrile (SF6847), bearing a cationic alkyl(triphenyl)phosphonium (TPP) group. As a key step of the synthesis, we used condensation of a ketophenol with malononitrile via the Knoevenagel reaction. SF-C5-TPP with a pentamethylene linker between SF6847 and TPP, stimulating respiration and collapsing membrane potential of rat liver mitochondria at submicromolar concentrations, proved to be the most effective uncoupler of the series. SF-C5-TPP showed pronounced protonophoric activity on a model planar bilayer lipid membrane. Importantly, SF-C5-TPP exhibited rather low toxicity in fibroblast cell culture, causing mitochondrial depolarization in cells at concentrations that only slightly affected cell viability. SF-C5-TPP was more effective in decreasing the mitochondrial membrane potential in the cell culture than SF6847, in contrast to the case of isolated mitochondria. Like other zwitterionic uncouplers, SF-C5-TPP inhibited the growth of Bacillus subtilis in the micromolar concentration range.

Novel Vitamin D3 Hydroxymetabolites Require Involvement of the Vitamin D Receptor or Retinoic Acid-Related Orphan Receptors for Their Antifibrogenic Activities in Human Fibroblasts.

We investigated multiple signaling pathways activated by CYP11A1-derived vitamin D3 hydroxymetabolites in human skin fibroblasts by assessing the actions of these molecules on their cognate receptors and by investigating the role of CYP27B1 in their biological activities. The actions of 20(OH)D3, 20,23(OH)2D3, 1,20(OH)2D3 and 1,20,23(OH)3D3 were compared to those of classical 1,25(OH)2D3. This was undertaken using wild type (WT) fibroblasts, as well as cells with VDR, RORs, or CYP27B1 genes knocked down with siRNA. Vitamin D3 hydroxymetabolites had an inhibitory effect on the proliferation of WT cells, but this effect was abrogated in cells with silenced VDR or RORs. The collagen expression by WT cells was reduced upon secosteroid treatment. This effect was reversed in cells where VDR or RORs were knocked down where the inhibition of collagen production and the expression of anti-fibrotic genes in response to the hydroxymetabolites was abrogated, along with ablation of their anti-inflammatory action. The knockdown of CYP27B1 did not change the effect of either 20(OH)D3 or 20,23(OH)2D3, indicating that their actions are independent of 1α-hydroxylation. In conclusion, the expression of the VDR and/or RORα/γ receptors in fibroblasts is necessary for the inhibition of both the proliferation and fibrogenic activity of hydroxymetabolites of vitamin D3, while CYP27B1 is not required.

Associations between e-cigarette marketing exposure and vaping nicotine and cannabis among U.S. adults, 2021.

Importance: Vaping has become an increasingly common method for consuming nicotine and cannabis, a trend potentially influenced by e-cigarette marketing. However, little is known about the influence of e-cigarette marketing on cannabis vaping behaviors. Objective: To examine the associations between e-cigarette marketing exposure and nicotine and cannabis vaping behaviors among adults. Design Setting and Participants: This cross-sectional study included a U.S. nationally representative sample of adults (≥18 years) from the Wave 6 survey of the Population Assessment of Tobacco and Health (PATH) Study, conducted from March to November 2021. Exposure: Past 30-day e-cigarette marketing exposure (overall and by ten marketing channels). Main Outcomes and Measures: Past 30-day vaping behavior (sole- and dual-vaping of nicotine and cannabis) overall and stratified by age. Results: The study included 30,516 respondents (48.0% male and 63.9% non-Hispanic White). Overall, 52.0% of respondents reported past 30-day e-cigarette marketing exposure, and 89.8%, 5.6%, 3.2%, and 1.4% reported no vaping, sole-nicotine vaping, sole-cannabis vaping, and dual-vaping, respectively. Multinominal logistic regression results show exposure to e-cigarette marketing was associated with increased odds of reporting sole-cannabis vaping versus no vaping (adjusted risk ratio [aRR], 1.31; 95% confidence interval [CI], 1.09-1.57) and dual-vaping versus no vaping (aRR, 1.26; 95% CI, 1.01-1.57). Stratification analysis found these associations among those aged 18-24 and 25-34 years but not older adults (≥35 years). Those exposed to e-cigarette marketing also had increased odds of reporting sole-cannabis vaping versus sole-nicotine vaping (aRR, 1.28; 95% CI, 1.04-1.58). Stratification analysis found this association only among those aged 18-24 years. E-cigarette marketing exposure via several channels (retail stores, billboards, events, newspapers/magazines) was associated with increased odds of reporting sole-cannabis vaping. Conclusions and Relevance: E-cigarette marketing exposure was only associated with sole-cannabis vaping and dual-vaping, not sole-nicotine vaping among U.S. adults. Such associations were mainly driven by young adults aged 18-24 and 25-35 years and were found for multiple marketing channels. Greater restrictions on tobacco marketing may have reduced the influence of e-cigarette marketing on nicotine vaping, while gaps in such marketing restrictions for cannabis may contribute to continued influence of e-cigarette marketing on cannabis vaping.

Methylation of Phenyl Rings in Ester-Stabilized Phosphorus Ylides Vastly Enhances Their Protonophoric Activity.

We have recently discovered that ester-stabilized phosphorus ylides, resulting from deprotonation of a phosphonium salt such as [Ph3PCH2COOR], can transfer protons across artificial and biological membranes. To create more effective cationic protonophores, we synthesized similar phosphonium salts with one ((heptyloxycarbonylmethyl)(p-tolyl)bromide) or two ((butyloxycarbonylmethyl)(3,5-xylyl)osphonium bromide) methyl substituents in the phenyl groups. The methylation enormously augmented both protonophoric activity of the ylides on planar bilayer lipid membrane (BLM) and uncoupling of mammalian mitochondria, which correlated with strongly accelerated flip-flop of their cationic precursors across the BLM.

Right Ventricular and Outflow Tract Functional Characteristics After Repair of Tetralogy of Fallot with Major Aortopulmonary Collaterals.

This study describes right ventricle (RV) characteristics and right ventricle to pulmonary artery (RV-PA) conduit function pre- and post-repair in patients with tetraology of Fallot with major aortopulmonary collaterals (TOF/MAPCAs). We reviewed patients who underwent single-stage, complete unifocalization, and repair of TOF/MAPCAs between 2006 and 2019 with available pre- and early postoperative echocardiograms. For a subset of patients, 6-12 month follow-up echocardiogram was available. RV and left ventricle (LV) characteristics and RV-PA conduit function were reviewed. Wilcoxon signed rank test and McNemar's test were used. 170 patients were reviewed, 46 had follow-up echocardiograms. Tricuspid valve annular plane systolic excursion (TAPSE) Z-scores were reduced from pre- (Z-score 0.01) to post-repair (Z-score -4.5, p < 0.001), improved but remained abnormal at follow-up (Z-score -4.0, p < 0.001). RV fractional area change (FAC) and LV ejection fraction were not significantly different before and after surgery. Conduit regurgitation was moderate or greater in 11% at discharge, increased to 65% at follow-up. RV-PA conduit failure (severe pulmonary stenosis or severe pulmonary regurgitation) was noted in 61, and 63% had dilated RV (diastolic RV area Z-score > 2) at follow-up. RV dilation correlated with the severe conduit regurgitation (p = 0.018). Longitudinal RV function was reduced after complete repair of TOF/MAPCAs, with decreased TAPSE and preserved FAC and LV ejection fraction. TAPSE improved but did not normalize at follow-up. Severe RV-PA conduit dysfunction was observed prior to discharge in 11% of patients and in 61% at follow-up. RV dilation was common at follow-up, especially in the presence of severe conduit regurgitation.

European common frogs determine migratory direction by inclination magnetic compass and show diurnal variation in orientation.

Animals can use two variants of the magnetic compass: the 'polar compass' or the 'inclination compass'. Among vertebrates, the compass type has been identified for salmon, mole rats, birds, turtles and urodeles. However, no experiments have been conducted to determine the compass variant in anurans. To elucidate this, we performed a series of field and laboratory experiments on males of the European common frog during the spawning season. In field experiments in a large circular arena, we identified the direction of the stereotypic migration axis for a total of 581 frogs caught during migration from river to pond or in a breeding pond. We also found that motivation of the frogs varied throughout the day, probably to avoid deadly night freezes, which are common in spring. The laboratory experiments were conducted on a total of 450 frogs in a T-maze placed in a three-axis Merritt coil system. The maze arms were positioned parallel to the natural migration axis inferred on the basis of magnetic field. Both vertical and horizontal components of the magnetic field were altered, and frogs were additionally tested in a vertical magnetic field. We conclude that European common frogs possess an inclination magnetic compass, as for newts, birds and sea turtles, and potentially use it during the spring migration. The vertical magnetic field confuses the frogs, apparently as a result of the inability to choose a direction. Notably, diurnal variation in motivation of the frogs was identical to that in nature, indicating the presence of internal rhythms controlling this process.

Neurophotonic methods in approach to in vivo animal epileptic models: Advantages and limitations.

Neurophotonic technology is a rapidly growing group of techniques that are based on the interactions of light with natural or genetically modified cells of the neural system. New optical technologies make it possible to considerably extend the tools of neurophysiological research, from the visualization of functional activity changes to control of brain tissue excitability. This opens new perspectives for studying the mechanisms underlying the development of human neurological diseases. Epilepsy is one of the most common brain disorders; it is characterized by recurrent seizures and affects >1% of the world's population. However, how seizures occur, spread, and terminate in a healthy brain is still unclear. Therefore, it is extremely important to develop appropriate models to accurately explore the causal relationship of epileptic activity. The use of neurophotonic technologies in epilepsy research falls into two broad categories: the visualization of neural epileptic activity, and the direct optical influence on neurons to induce or suppress epileptic activity. An optogenetic variant of the classical kindling model of epileptic seizures, in which activatable cells are genetically defined, is called optokindling. Research is also underway concerning the application of neurophotonic techniques for suppressing epileptic activity, aiming to bring these methods into clinical practice. This review aims to systematize and describe new approaches that use combinations of different neurophotonic methods to work with in vivo models of epilepsy. These approaches overcome many of the shortcomings associated with classical animal models of epilepsy and thus increase the effectiveness of developing new diagnostic methods and antiepileptic therapy.

Why Start Now? Retrospective Study Evaluating Baseline Screening Mammography in Patients Age 60 and Older.

PURPOSE: Extensive data exist regarding the importance of baseline mammography and screening recommendations in the age range of 40-50 years old, however, less is known about women who start screening at age 60. The purpose of this retrospective study is to assess the characteristics and outcomes of women aged 60 years and older presenting for baseline mammographic screening. METHODS: This is an IRB-approved single institution retrospective review of data from patients aged 60+ receiving baseline screening mammograms between 2010 and 2022 was obtained. Information regarding patient demographics, breast density, and BI-RADS assessment was acquired from Cerner EHR. Of patients with a BI-RADS 0 assessment, imaging, and chart review was performed. Family history, gynecologic history, prior breast biopsy or surgery, and hormone use was reviewed. For those with a category 4 or 5 assessment after diagnostic work-up, biopsy outcomes were reported. Cancer detection rate (CDR), recall rate (RR), positive predictive value 1 (PPV1), PPV2, and PPV3 were calculated. RESULTS: Data was analyzed from 1409 women over age 60 who underwent breast cancer screening. The recall rate was 29.3% (413/1409). The CDR, PPV1, PPV2, and PPV3 were calculated as 15/1000, 5.2% (21/405), 29.2% (21/72), and 31.8% (21/66), respectively. After work-up, 224 diagnostic patients had a 1-year follow-up and none were diagnosed with breast cancer. One (1.4%, 1/71) of the BI-RADS 3 lesions was malignant at 2-year follow-up. Of the patients recalled from screening, 29.6% had a family history of breast cancer, and the majority of both recalled and nonrecalled patients had Category B breast density. There was no statistically significant difference in breast density or race of patients recalled vs not recalled. 93.2% of recalled cases were given BI-RADS descriptors, with mass and focal asymmetry being the most common lesions, and 22.1% of recalled cases included more than one lesion. CONCLUSION: Initiating screening mammography for patients over 60 years old may result in higher recall rates, but also leads to a high CDR of potentially clinically relevant invasive cancers. After a diagnostic work-up, BI-RADS 3 assessments are within standard guidelines. This study provides guidance for radiologists reading baseline mammograms and clinicians making screening recommendations in patients over age 60.

The critical role of mitochondrial lipid peroxidation in ferroptosis: insights from recent studies.

Ferroptosis is a regulated form of necrotic cell death reliant on iron-catalyzed lipid peroxidation. Although the precise involvement of mitochondria in ferroptosis remains incompletely elucidated, recent research indicates that mitochondrial oxidative events wield a pivotal influence in this mechanism. This article centers on the most recent discoveries, spotlighting the significance of mitochondrial lipid peroxidation in the occurrence of ferroptosis. Modern investigative tools, such as mitochondria-specific dyes responsive to lipid peroxidation and antioxidants targeting mitochondria, have been employed to delve into this phenomenon. The authors' recent empirical evidence demonstrates that mitochondrial lipid peroxidation, quantified using the innovative fluorescent ratiometric probe MitoCLox, takes place prior to the onset of ferroptotic cell death. The mitochondria-targeted antioxidant SkQ1 hinders mitochondrial lipid peroxidation and thwarts ferroptosis, all while leaving unaffected the buildup of reactive oxygen species within the cytoplasm, an antecedent to mitochondrial lipid peroxidation. Similarly, the redox agent methylene blue, impeding the genesis of reactive oxygen species in complex I of the electron transport chain, also imparts a comparable protective effect. These findings collectively imply that reactive oxygen species originating from complex I might hold particular significance in fomenting mitochondrial lipid peroxidation, a pivotal trigger of ferroptosis.

Cannabis Vape Product Sales in California Following CDC's Initial Advisory About Lung Injuries.

Introduction: The 2019 outbreak of e-cigarette or vaping product use-associated lung injury (EVALI) is believed to have been caused by vitamin E acetate, an additive used in some cannabis vaporizer products. Previous studies have primarily focused on changes in sales of electronic nicotine delivery systems following the initial advisory issued by the Centers for Disease Control (CDC) on August 17, 2019. The present study is intended to examine variation by age groups in sales of regulated cannabis vape products in the state of California before, during, and after the outbreak. Methods: Weekly sales revenue of cannabis vape products (from January 1, 2018, to December 31, 2020) was obtained from a sample of recreational cannabis retailers licensed in California. An interrupted time series analysis, using AutoRegressive, Integrated, Moving Average methods, was employed to estimate changes in the sales and market share of cannabis vape products in the weeks following the CDC advisory. Results: The total volume of regulated cannabis vape product sales increased substantially over the 3-year study period (2018-2020). Sales and market share of cannabis vape products, however, declined in both young and older adults immediately following the advisory, rebounding to pre-EVALI levels only for the young adults. For sales, the potential EVALI effect following the CDC's advisory equates to an 8.0% and 2.2% decline below expected levels in the older and young adults, respectively. Conclusions: The differential age effect on sales may reflect concerns regarding health effects of cannabis vaping products and greater awareness of the outbreak among older adults. Findings highlight the importance of informing consumers about health risks associated with using cannabis vape products acquired from regulated versus illicit sources.