Effect of estrogen depression on alveolar bone microarchitecture and periodontal ligament cells during orthodontic movement.

This study aimed to evaluate the effects of the estrogen depression during orthodontic tooth movement on alveolar bone microarchitecture and periodontal ligament. Female Wistar rats were divided into two groups, one consisting of non-ovariectomized animals subjected to orthodontic tooth movement, and one comprising ovariectomized animals subjected to orthodontic tooth movement. Micro-CT assessment of bone volume to total volume (BV/TV), total porosity, trabecular thickness (Tb.Th), trabecular number (Tb.N), and trabecular separation (Tb.Sp) in the alveolar bone of the orthodontically moved tooth was performed. Histomorphometric analyses were made in the periodontal ligament, and immunoexpression of RANK, RANKL, OPG, and TUNEL were quantified. Orthodontic tooth movement in the group of ovariectomized rats was faster than in non-ovariectomized animals. The alveolar bone area showed lower values of BV/TV and trabecular thickness, and higher bone porosity and trabeculae numbers in the ovariectomized rats. Histological analyses in the ovariectomized group revealed an increase in collagen fibers in the periodontal ligament. The apoptotic cell counts in the periodontal ligament were higher in the group of ovariectomized rats than in the sham-operated rats. Ovariectomy resulted in an increase in tooth movement and alteration of the alveolar bone microstructure in the first 7 day of orthodontic tooth movement, and in the presence of apoptotic cells in the periodontal ligament.

Direct determination of POSS cage structure in a self-assembled ionic bridged silsesquioxane by using the total pair distribution function G(r) and density functional theory.

In the present study, both short-range and long-range structural features of an ionic bridged silsesquioxane, specifically one containing the 1,4-diazoniabicyclo[2.2.2]octane chloride group (ISSQ), were elucidated. This ionic silsesquioxane was synthesized via direct polycondensation of a bridged organosilane precursor, without any additional functionalization step. Si-O-Si cage structures typical of Polyhedral Oligomeric Silsesquioxanes (POSS) were identified. The average interatomic distances of the POSS cages, including the open T8 cage and the T12 cage for the ISSQ, as well as the T8 cage for a commercially available pendant POSS were determined. It is the first report of the interatomic distance determination of POSS cage; achieved by using total pair distribution function G(r) values obtained through high-resolution synchrotron X-ray diffraction combined with density functional theory (DFT) calculations. The application of DFT was crucial for accurately assigning X-ray peaks and verifying structural details. Furthermore, the analysis of X-ray diffraction peaks and the examination of crystalline domains via transmission electron microscopy enabled the proposal of a hexagonal arrangement of Si-O-Si cages over long ranges within the ionic bridged silsesquioxane. This proposed arrangement highlights a distinctive structural organization that could impact the material's properties and applications.

Which Variables Are Associated with the Magnitude of the Physical Fitness Response in Older Adults? An Analysis of Their Development and Influence.

Regular physical exercise has proven to be an effective strategy for enhancing the health and well-being of older adults. However, there are still gaps in our understanding of the impacts of exercise on older adults with different health conditions, as well as in the customization of training programs according to individual capabilities. This study aimed to analyze the variables that influence the response of physical capabilities in older adults, considering their development over the aging process, with the goal of assisting professionals in creating personalized training programs. To achieve this, we conducted a cohort study involving 562 previously inactive adults and older adults who underwent anthropometric assessments, blood pressure measurements, and comprehensive physical tests. These assessments were conducted before and after a 14-week training program. Results indicated no significant variations in variables such as waist circumference (p = 0.0455, effect size = 0.10), body mass index (p = 0.0215, effect size = 0.15), systolic (p < 0.0001, effect size = 0.35) and diastolic blood pressure (p < 0.0001, effect size = 0.25) pre- and post-intervention. Strength tests, agility, the 6 min walk test (6MWT), and the back scratch test (BS) showed significant improvements post-intervention, with p-values all below 0.0001 and effect sizes ranging from 0.30 to 0.50. Multiple linear regression analyses revealed that lower initial values in physical capabilities were associated with more significant improvements during training (R2 = 0.73, p < 0.001). These results underscore that individualized guidance in training can lead to clinically meaningful improvements in physical performance and health among older adults, with effect sizes indicating moderate-to-large benefits (effect size range = 0.30 to 0.50). Therefore, personalized training programs are essential to maximize health benefits in this population.

Midbrain Cavernous Malformation: Microsurgical Nuances and an Anatomoclinical Review 2-Dimensional Video.

Midbrain cavernous malformations (MCMs) are rare and dangerous taken the important structures and tracts located in this segment of the brainstem. MCM treatment is still controversial, and surgical resection is basically indicated in cases of recurrent hemorrhage and progressive neurologic deterioration. The optimal moment to operate ruptured MCM is in the subacute stage. Once indicated for surgical resection, preoperative planning needs to be individualized. There are various ways to access midbrain lesions, depending on the extension and predominant location: lateral subtemporal, posterior transtentorial, interhemispheric transcallosal, and anterior temporopolar approaches, or some of the alternatives. The aim of this Video 1 case is to review the surrounding anatomic structures and demonstrate the advantages of the semisitting position and the viability of the supracerebellar infratentorial approach for a tegmental midbrain lesion.1-10 In this 2-dimensional video, we present an 18-year-old man with a 4-year history of diplopia and third nerve palsy, which worsened 10 days before admission. He underwent microsurgical total resection of this MCM via extreme lateral supracerebellar infratentorial approach in a semisitting position. At the end, the surgical site and surrounding structures were reviewed microscopically and endoscopically. The patient tolerated the surgery well, and the perioperative course was uneventful. His recovery was smooth but he maintained the previous oculomotor nerve palsy. We discuss important steps of the surgical approach, local neuroanatomy, and the microsurgical techniques for the resection of these challenging MCM. The goal is total resection of the MCM with the preservation of the developmental venous anomaly and the surrounding white fiber tracts.

Brain Perception of Different Oils on Appetite Regulation: An Anorectic Gene Expression Pattern in the Hypothalamus Dependent on the Vagus Nerve.

(1) Background: We examined the effect of the acute administration of olive oil (EVOO), linseed oil (GLO), soybean oil (SO), and palm oil (PO) on gastric motility and appetite in rats. (2) Methods: We assessed food intake, gastric retention (GR), and gene expression in all groups. (3) Results: Both EVOO and GLO were found to enhance the rate of stomach retention, leading to a decrease in hunger. On the other hand, the reduction in food intake caused by SO was accompanied by delayed effects on stomach retention. PO caused an alteration in the mRNA expression of NPY, POMC, and CART. Although PO increased stomach retention after 180 min, it did not affect food intake. It was subsequently verified that the absence of an autonomic reaction did not nullify the influence of EVOO in reducing food consumption. Moreover, in the absence of parasympathetic responses, animals that received PO exhibited a significant decrease in food consumption, probably mediated by lower NPY expression. (4) Conclusions: This study discovered that different oils induce various effects on parameters related to food consumption. Specifically, EVOO reduces food consumption primarily through its impact on the gastrointestinal tract, making it a recommended adjunct for weight loss. Conversely, the intake of PO limits food consumption in the absence of an autonomic reaction, but it is not advised due to its contribution to the development of cardiometabolic disorders.

Novel Relaxin Receptor RXFP1 Agonist AZD3427 in the Treatment of Heart Failure: A Phase 1a/b, First-in-Human, Randomized, Single-Blind, Placebo-Controlled Study.

BACKGROUND: Heart failure mortality remains high despite recent progress in pharmacological treatment. AZD3427 is a selective long-acting analog of relaxin, a vasodilatory hormone with antifibrotic effects. We assessed the safety, pharmacokinetics, and pharmacodynamics of AZD3427 in healthy volunteers and patients with heart failure on standard-of-care therapy. METHODS AND RESULTS: In this first-in-human, phase 1a/b, randomized, single-blind, placebo-controlled study, healthy volunteers were randomized 6:2 to receive a single dose of AZD3427 or placebo by subcutaneous injection in 5 mixed-ethnicity cohorts (5, 10, 30, 90, or 270 mg) and 1 Japanese-descent cohort (270 mg), or by intravenous injection in 1 cohort (15 mg). After confirming safety and tolerability in healthy volunteers, 3 cohorts of patients with heart failure and left ventricular ejection fraction ≤40% and 3 cohorts with ejection fraction ≥41% were randomized 6:2 to receive 5 weekly doses of AZD3427 (5, 15, or 45 mg) or placebo by subcutaneous injection. In total, 56 healthy volunteers and 48 patients with heart failure were randomized. AZD3427 was well tolerated at all doses. After subcutaneous administration, AZD3427 was absorbed slowly, and exposure was approximately linear across the dose range. In patients with heart failure, AZD3427 terminal half-life was 13 to 14 days and there were numerical increases in stroke volume and estimated glomerular filtration rate. No treatment-emergent antidrug antibodies were detected. CONCLUSIONS: AZD3427 had favorable safety and pharmacokinetic profiles. Hemodynamic changes in patients with heart failure were consistent with the anticipated effects of a relaxin analog. These findings support further development of AZD3427 as a novel long-term treatment for patients with heart failure. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04630067.

Combined exercise training decreases blood pressure in OLDER women with NOS3 polymorphism providing changes in differentially methylated regions (DMRs).

The mechanisms by which the ageing process is associated to an unhealthy lifestyle and how they play an essential role in the aetiology of systemic arterial hypertension have not yet been completely elucidated. Our objective is to investigate the influence of NOS3 polymorphisms [-786T > C and (Glu298Asp)] on systolic blood pressure (SBP) and diastolic blood pressure (DBP) response, differentially methylated regions (DMRs), and physical fitness of adult and older women after a 14-week combined training intervention. The combined training was carried out for 14 weeks, performed 3 times a week, totalling 180 minutes weekly. The genotyping experiment used Illumina Infinium Global Screening Array version 2.0 (GSA V2.0) and Illumina's EPIC Infinium Methylation BeadChip. The participants were separated into SNP rs2070744 in TT (59.7 ± 6.2 years) and TC + CC (60.0 ± 5.2 years), and SNP rs17999 in GluGlu (58.8 ± 5.7 years) and GluAsp + AspAsp (61.6 ± 4.9 years). We observed an effect of time for variables BP, physical capacities, and cholesterol. DMRs related to SBP and DBP were identified for the rs2070744 and rs17999 groups pre- and decreased numbers of DMRs post-training. When we analysed the effect of exercise training in pre- and post-comparisons, the GluGlu SNP (rs17999) showed 10 DMRs, and after enrichment, we identified several biological biases. The combined training improved the SBP and DBP values of the participants regardless of the SNPs. In addition, exercise training affected DNA methylation differently between the groups of NOS3 polymorphisms.

Differential Stroke Volume between Left and Right Ventricles as a Predictor of Clinical Outcomes: The MESA Study.

Background Valvular heart disease and intracardiac shunts can disrupt the balance between left ventricular (LV) and right ventricular (RV) stroke volumes. However, the prognostic value of such imbalances has not been established among asymptomatic individuals. Purpose To assess the association between differential ventricular stroke volumes quantified using cardiac MRI and clinical outcomes in individuals without cardiovascular disease. Materials and Methods This secondary analysis of a prospective study included participants without cardiovascular disease at enrollment (July 2000 to July 2002) who underwent cardiac MRI. Differences in stroke volume were calculated as LV stroke volume minus RV stroke volume, and participants were categorized as having balanced (greater than or equal to -30 mL to ≤30 mL), negative (less than -30 mL), or positive (>30 mL) differential stroke volumes. Multivariable Cox proportional hazard regression models were used to test the association between differences in stroke volume and adverse outcomes. Results A cohort of 4058 participants (mean age, 61.4 years ± 10 [SD]; 2120 female) were included and followed up for a median of 18.4 years (IQR, 18.3-18.5 years). During follow-up, 1006 participants died, 235 participants developed heart failure, and 764 participants developed atrial fibrillation. Compared with participants who had a balanced differential stroke volume, those with an increased differential stroke volume showed a higher risk of mortality (hazard ratio [HR], 1.73 [95% CI: 1.12, 2.67]; P = .01), heart failure (HR, 2.40 [95% CI: 1.11, 5.20]; P = .03), and atrial fibrillation (HR, 1.89 [95% CI: 1.16, 3.08]; P = .01) in adjusted models. Participants in the negative group, with a decreased differential stroke volume, showed an increased risk of heart failure compared with those in the balanced group (HR, 2.09 [95% CI: 1.09, 3.99]; P = .03); however, this was no longer observed after adjusting for baseline LV function (P = .34). Conclusion Participants without cardiovascular disease at the time of study enrollment who had an LV stroke volume exceeding the RV stroke volume by greater than 30 mL had an increased risk of mortality, heart failure, and atrial fibrillation compared with those with balanced stroke volumes. ClinicalTrials.gov Identifier: NCT00005487 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Almeida in this issue.

Change in left atrial function and volume predicts incident heart failure with preserved and reduced ejection fraction: Multi-Ethnic Study of Atherosclerosis.

AIMS: The role of change in left atrial (LA) parameters prior to the onset of heart failure (HF) remains unclear. We used cardiac magnetic resonance (CMR) imaging to investigate the relationship between longitudinal change in LA function and incident HF in a multi-ethnic population with subclinical cardiovascular disease (CVD). METHODS AND RESULTS: In this prospective multi-ethnic cohort study, 2470 participants (60 ± 9 years, 47% males), free at baseline of clinical CVD, had LA volume and function assessed via multimodality tissue tracking on CMR imaging at baseline (2000-02) and a second study 9.4 ± 0.6 years later. Free of HF, 73 participants developed incident HF [HF with preserved ejection fraction (HFpEF), n = 39; reduced ejection fraction (HFrEF), n = 34] 7.1 ± 2.1 years after the second study. An annual decrease of 1 SD unit in peak LA strain (ΔLASmax) was most strongly associated with the risk of HFpEF [subdistribution hazard ratios (HR) = 2.56, 95% confidence interval (CI) (1.34-4.90), P = 0.004] and improved model reclassification and discrimination in predicting HFpEF [C-statistic = 0.84, 95% CI (0.79-0.90); net reclassification index (NRI) = 0.34, P = 0.01; and integrated discrimination index (IDI) = 0.02, P = 0.02], whilst an annual decrease of 1 mL/m2 of pre-atrial indexed LA volumes (ΔLAVipreA) was most strongly associated with the risk of HFrEF [subdistribution HR = 1.88, 95% CI (1.44-2.45), P < 0.001] and improved model reclassification and discrimination in predicting HFrEF [C-statistic = 0.81, 95% CI (0.72-0.90); NRI = 0.31, P = 0.03; and IDI = 0.01, P = 0.50] after adjusting for event-specific risk factors and baseline LA measures. CONCLUSION: ΔLASmax and ΔLAVipreA were associated with and incrementally predictive of HFpEF and HFrEF, after adjusting for risk factors and baseline LA measures in this population of subclinical CVD.

Association of endogenous sex hormone levels with tooth loss due to periodontitis in men and post-menopausal women: The multi-ethnic study of atherosclerosis.

AIM: To investigate the association between endogenous sex hormone levels and history of tooth loss related to periodontitis in healthy middle-aged to older men and post-menopausal women. METHODS: This cross-sectional study included 5649 participants aged 45-84 (mean age, 63 ± 10 years) from the Multi-Ethnic Study of Atherosclerosis cohort who had sex hormone levels measured and answered a questionnaire regarding perceived periodontal status at exam 1. Multivariable logistic regression was used to examine the association of sex hormones (exposure) with history of tooth loss (outcome), stratified by sex. RESULTS: Among post-menopausal women, higher free testosterone (per 1SD) was associated with a greater prevalence of tooth loss [OR 1.49 (95% CI, 1.08-2.05)], whereas higher sex hormone binding globulin (SHBG) was associated with a lower prevalence of tooth loss [OR 0.74 (0.58-0.94)], after adjustment for cardiometabolic risk factors and reproductive factors. In men, higher free testosterone and lower SHBG were associated with a lower prevalent probability of tooth loss in unadjusted analysis, but these associations lost significance after covariate adjustment. CONCLUSION: A higher androgenic sex hormone profile in post-menopausal women (i.e., increased free testosterone, lower SHBG) was associated with an increased prevalence of tooth loss, after adjusting cardiometabolic risk factors. No such association was found in men. These findings suggest that sex hormones may influence or serve as a marker for periodontal health.

Bacteriocinogenic anti-listerial properties and safety assessment of Enterococcus faecium and Lactococcus garvieae strains isolated from Brazilian artisanal cheesemaking environment.

AIMS: This study aimed to prospect and isolate lactic acid bacteria (LAB) from an artisanal cheese production environment, to assess their safety, and to explore their bacteriocinogenic potential against Listeria monocytogenes. METHODS AND RESULTS: Samples were collected from surfaces of an artisanal-cheese production facility and after rep-PCR and 16S rRNA sequencing analysis, selected strains were identified as to be belonging to Lactococcus garvieae (1 strain) and Enterococcus faecium (14 isolates, grouped into three clusters) associated with different environments (worktables, cheese mold, ripening wooden shelves). All of them presented bacteriocinogenic potential against L. monocytogenes ATCC 7644 and were confirmed as safe (γ-hemolytic, not presenting antibiotic resistance, no mucus degradation properties, and no proteolytic or gelatinase enzyme activity). Additionally, cell growth, acidification and bacteriocins production kinetics, bacteriocin stability in relation to different temperatures, pH, and chemicals were evaluated. According to performed PCR analysis all studied strains generated positive evidence for the presence of entA and entP genes (for production of enterocins A and enterocins P, respectively). However, pediocin PA-1 associated gene was recorded only in DNA obtained from E. faecium ST02JL and Lc. garvieae ST04JL. CONCLUSIONS: It is worth considering the application of these safe LAB or their bacteriocins in situ as an alternative means of controlling L. monocytogenes in cheese production environments, either alone or in combination with other antimicrobials.

Empiric antibiotic regimens in adults with non-ventilator-associated hospital-acquired pneumonia: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: The optimal empiric antibiotic regimen for non-ventilator-associated hospital-acquired pneumonia (HAP) is uncertain. OBJECTIVES: To compare the effectiveness and safety of alternative empiric antibiotic regimens in HAP using a network meta-analysis. DATA SOURCES: Medline, EMBASE, Cochrane CENTRAL, Web of Science, and CINAHL from database inception to July 06, 2023. STUDY ELIGIBILITY CRITERIA: RCTs. PARTICIPANTS: Adults with clinical suspicion of HAP. INTERVENTIONS: Any empiric antibiotic regimen vs. another, placebo, or no treatment. ASSESSMENT OF RISK OF BIAS: Paired reviewers independently assessed risk of bias using a modified Cochrane tool for assessing risk of bias in randomized trials. METHODS OF DATA SYNTHESIS: Paired reviewers independently extracted data on trial and patient characteristics, antibiotic regimens, and outcomes of interest. We conducted frequentist random-effects network meta-analyses for treatment failure and all-cause mortality and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Thirty-nine RCTs proved eligible. Thirty RCTs involving 4807 participants found low certainty evidence that piperacillin-tazobactam (RR compared to all cephalosporins: 0.65; 95% CI: 0.42, 1.01) and carbapenems (RR compared to all cephalosporins: 0.77; 95% CI: 0.53, 1.11) might be among the most effective in reducing treatment failure. The findings were robust to the secondary analysis comparing piperacillin-tazobactam vs. antipseudomonal cephalosporins or antipseudomonal carbapenems vs. antipseudomonal cephalosporins. Eleven RCTs involving 2531 participants found low certainty evidence that ceftazidime and linezolid combination may not be convincingly different from cephalosporin alone in reducing all-cause mortality. Evidence on other antibiotic regimens is very uncertain. Data on other patient-important outcomes including adverse events was sparse, and we did not perform network or pairwise meta-analysis. CONCLUSIONS: For empiric antibiotic therapy of adults with HAP, piperacillin-tazobactam might be among the most effective in reducing treatment failure. Empiric methicillin-resistant Staphylococcus aureus coverage may not exert additional benefit in reducing mortality. REGISTRATION: PROSPERO (CRD 42022297224).

The Impact of Silent Liver Disease on Hospital Length of Stay Following Isolated Coronary Artery Bypass Grafting Surgery.

Objectives: Risk assessment models for cardiac surgery do not distinguish between degrees of liver dysfunction. We have previously shown that preoperative liver stiffness is associated with hospital length of stay following cardiac surgery. The authors hypothesized that a liver stiffness measurement (LSM) ≥ 9.5 kPa would rule out a short hospital length of stay (LOS < 6 days) following isolated coronary artery bypass grafting (CABG) surgery. Methods: A prospective observational study of one hundred sixty-four adult patients undergoing non-emergent isolated CABG surgery at a single university hospital center. Preoperative liver stiffness measured by ultrasound elastography was obtained for each participant. Multivariate logistic regression models were used to assess the adjusted relationship between LSM and a short hospital stay. Results: We performed multivariate logistic regression models using short hospital LOS (<6 days) as the dependent variable. Independent variables included LSM (< 9.5 kPa, ≥ 9.5 kPa), age, sex, STS predicted morbidity and mortality, and baseline hemoglobin. After adjusting for included variables, LSM ≥ 9.5 kPa was associated with lower odds of early discharge as compared to LSM < 9.5 kPa (OR: 0.22, 95% CI: 0.06-0.84, p = 0.03). The ROC curve and resulting AUC of 0.76 (95% CI: 0.68-0.83) suggest the final multivariate model provides good discriminatory performance when predicting early discharge. Conclusions: A preoperative LSM ≥ 9.5 kPa ruled out a short length of stay in nearly 80% of patients when compared to patients with a LSM < 9.5 kPa. Preoperative liver stiffness may be a useful metric to incorporate into preoperative risk stratification.

Nontraditional Risk Markers for Incident Coronary Artery Calcium Among Persons ≥65 Years of Age.

Background: The initiation of coronary artery calcium (CAC) is an important physiologic milestone associated with increased cardiovascular disease risk. However, traditional risk factors (RF) do not perform well for predicting incident CAC among the 54 million older U.S. adults. Objectives: The authors sought to assess the association between nontraditional cardiovascular disease RF and incident CAC in older persons. Methods: There were 815 MESA (Multi-Ethnic Study of Atherosclerosis) participants ≥65 years of age who had CAC = 0 at Visit 1 and a follow-up CAC scan. Multivariable adjusted Cox hazards ratios (aHR) and C-statistics were calculated to examine the association of nontraditional RF with incident CAC. Results: The mean age was 70.2 years and 67% were women. The median follow-up time to repeat CAC scan was 3.6 years (IQR: 2.6-9.2 years) and 45% of participants developed incident CAC. Albuminuria (aHR: 1.50, 95% CI: 1.07-2.09), carotid plaque (aHR: 1.32, 95% CI: 1.04-1.66), and thoracic aortic calcification (TAC) (aHR: 1.38, 95% CI: 1.10-1.75) were significantly associated with incident CAC, while higher levels of nontraditional RF including apolipoprotein-B, lipoprotein(a), high-sensitivity troponin T, and N-terminal pro-brain natriuretic peptide were not. When added to demographics, albuminuria, carotid plaque, and TAC provided a greater C-statistic improvement (+0.047, P = 0.004) vs all traditional RF combined (+0.033, P = 0.05). Conclusions: Among nontraditional RF and measures of subclinical atherosclerosis, only albuminuria, carotid plaque, and TAC were significantly associated with incident CAC in persons ≥65 years of age. Identification of albuminuria or extracoronary atherosclerosis may help guide the timing of repeat CAC scoring in older persons with baseline CAC = 0.

Towards efficient Ir(III) anticancer photodynamic therapy agents by extending π-conjugation on N

In this work we disclose a new family of biscyclometallated Ir(III) complexes of the general formula [Ir(C^N)2(N^N)]Cl (IrL1-IrL5), where HC^N is 1-phenyl-ß-carboline and N^N ligands (L1-L5) are different diimine ligands that differ from each other in the number of aromatic rings fused to the bipyridine scaffold. The photophysical properties of IrL1-IrL5 were thoroughly studied, and theoretical calculations were performed for a deeper comprehension of the respective variations along the series. All complexes exhibited high photostability under blue light irradiation. An increase in the number of aromatic rings led to a reduction in the HOMO-LUMO band gap causing a red-shift in the absorbance bands. Although all the complexes generated singlet oxygen (1O2) in aerated aqueous solutions through a photocatalytic process, IrL5 was by far the most efficient photosensitizer. Consequently, IrL5 was highly active in the photocatalytic oxidation of NADH. The formation of aggregates in DMSO at a high concentration (25 mM) was confirmed using different techniques, but was proved to be negligible in the concentration range of biological experiments. Moreover, ICP-MS studies proved that the cellular uptake of IrL2 and IrL3 is much better relative to that of IrL1, IrL4 and IrL5. The antiproliferative activity of IrL1-IrL5 was investigated in the dark and under blue light irradiation against different cancer cell lines. Complexes IrL1-IrL4 were found to be cytotoxic under dark conditions, while IrL5 turned out to be weakly cytotoxic. Despite the low cellular uptake of IrL5, this derivative exhibited a high increase of cytotoxicity upon blue light irradiation resulting in photocytotoxicity indexes (PI) up to 38. IrL1-IrL4 showed lower photocytotoxicity indexes ranging from 1.3 to 17.0. Haemolytic experiments corroborated the compatibility of our complexes with red blood cells. Confocal microscopy studies proved their accumulation in mitochondria, leading to mitochondrial membrane depolarization, and ruled out their localization in lysosomes. Overall, the mitochondria-targeted activity of IrL5, which inhibits considerably the viability of cancer cells upon blue light irradiation, allows us to outline this PS as a new alternative to traditional chemotherapeutic agents.

Inhibition of the morphological transition of Candida spp. by riparins I-IV.

Candida spp. is an opportunistic pathogen capable of causing superficial to invasive infections. Morphological transition is one of the main virulence factors of this genus and, therefore, is an important variable to be considered in pharmacological interventions. Riparins I, II, III, and IV are alkamide-type alkaloids extracted from the unripe fruit of Aniba riparia, whose remarkable pharmacological properties were previously demonstrated. This work aimed to evaluate in silico and in vitro the inhibitory effects of Riparins on the morphological transition of Candida albicans, Candida tropicalis, and Candida krusei. Molecular docking was applied to analyze the inhibitory effects of riparins against proteins such as N-acetylglucosamine, CYP-51, and protein kinase A (PKA) using the Ramachandran plot. The ligands were prepared by MarvinSketch and Spartan software version 14.0, and MolDock Score and Rerank Score were used to analyze the affinity of the compounds. In vitro analyses were performed by culturing the strains in humid chambers in the presence of riparins or fluconazole (FCZ). The morphology was observed through optical microscopy, and the size of the hyphae was determined using the ToupView software. In silico analysis demonstrated that all riparins are likely to interact with the molecular targets: GlcNAc (>50%), PKA (>60%), and CYP-51 (>70%). Accordingly, in vitro analysis showed that these compounds significantly inhibited the morphological transition of all Candida strains. In conclusion, this study demonstrated that riparins inhibit Candida morphological transition and, therefore, can be used to overcome the pathogenicity of this genus.

Advancing molecular modeling and reverse vaccinology in broad-spectrum yellow fever virus vaccine development.

Yellow fever outbreaks are prevalent, particularly in endemic regions. Given the lack of an established treatment for this disease, significant attention has been directed toward managing this arbovirus. In response, we developed a multiepitope vaccine designed to elicit an immune response, utilizing advanced immunoinformatic and molecular modeling techniques. To achieve this, we predicted B- and T-cell epitopes using the sequences from all structural (E, prM, and C) and nonstructural proteins of 196 YFV strains. Through comprehensive analysis, we identified 10 cytotoxic T-lymphocyte (CTL) and 5T-helper (Th) epitopes that exhibited overlap with B-lymphocyte epitopes. These epitopes were further evaluated for their affinity to a wide range of human leukocyte antigen system alleles and were rigorously tested for antigenicity, immunogenicity, allergenicity, toxicity, and conservation. These epitopes were linked to an adjuvant ( ß -defensin) and to each other using ligands, resulting in a vaccine sequence with appropriate physicochemical properties. The 3D structure of this sequence was created, improved, and quality checked; then it was anchored to the Toll-like receptor. Molecular Dynamics and Quantum Mechanics/Molecular Mechanics simulations were employed to enhance the accuracy of docking calculations, with the QM portion of the simulations carried out utilizing the density functional theory formalism. Moreover, the inoculation model was able to provide an optimal codon sequence that was inserted into the pET-28a( +) vector for in silico cloning and could even stimulate highly relevant humoral and cellular immunological responses. Overall, these results suggest that the designed multi-epitope vaccine can serve as prophylaxis against the yellow fever virus.

Association of Cardiovascular Fibrosis, Remodeling, and Dysfunction With Frailty, Prefrailty, and Functional Performance: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Cardiovascular disease is associated with higher incidence of frailty. However, the nature of the mechanisms underlying this association remains unclear. The purpose of this study is to identify cardiovascular phenotypes most associated with physical frailty and functional performance in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: As part of the MESA study, 3 045 participants underwent cardiovascular magnetic resonance and computed tomography between 2010 and 2012. Of these, 1 743 completed a Six-Minute Walk test (6MWT) and questionnaires (follow-up exam: 2016-2018) which were used to generate a binary combined frail/prefrail versus robust score according to a modified FRAIL Scale (self-report questionnaire). Multivariable logistic (binary frail outcome) or linear (6MWT) regression assessed the association between frailty and cardiovascular structure and function, aortic stiffness, coronary artery calcium, and myocardial fibrosis (ECV, extracellular volume fraction). RESULTS: Participants were 66 ±â€…8 years, 52% female at the time of imaging, and 29.4% were classified as frail or prefrail. Older age and female gender were associated with greater odds of being in the frail/prefrail group. Concentric left ventricular remodeling (odds ratio [OR] 1.89, p = .008; Coef. -52.9, p < .001), increased ECV (OR 1.10, p = .002; Coef. -4.0, p = .001), and worsening left atrial strain rate at early diastole (OR 1.56, p ≤ .001; Coef. -22.75, p = .027) were found to be associated with a greater likelihood of being in a frail state and lower 6MWT distance (m). All associations with 6MWT performance were attenuated with adjustments for risk factors whereas ECV and LA strain rate remained independently associated with frailty. CONCLUSIONS: These findings suggest a significant overlap in pathways associated with subclinical cardiac dysfunction, cardiovascular fibrosis, and physical frailty.

Associations between epicardial, visceral, and subcutaneous adipose tissue with diastolic function in men with and without HIV.

BACKGROUND: People with HIV (PWH) are at greater risk for diastolic dysfunction compared with persons without HIV (PWOH). An increase in visceral adipose tissue is common among PWH and greater visceral adipose tissue is associated with diastolic dysfunction among PWOH. We investigated associations of visceral adipose tissue, subcutaneous adipose tissue, and other fat depots with subclinical diastolic dysfunction among men with and without HIV (MWH and MWOH). DESIGN: Cross-sectional analysis of MWH and MWOH in the Multicenter AIDS Cohort Study (MACS). METHODS: Participants underwent echocardiography for diastolic dysfunction assessment and CT scanning including subcutaneous, visceral, epicardial, and liver adiposity measurements. Diastolic dysfunction was defined by characterizing heart function on antiretroviral therapy0 criteria. Odds for diastolic dysfunction with each measure of adiposity were estimated using multivariable logistic regression. RESULTS: Among 403 participants (median age 57, 55% white, median BMI 26 kg/m 2 ), 25% met criteria for diastolic dysfunction and 59% MWH (82% undetectable plasma HIV RNA). Greater epicardial adipose tissue area was associated with higher odds of diastolic dysfunction [odds ratio:1.54 per SD; 95%confidence interval (CI) 1.15-2.05] when adjusted for demographics, HIV serostatus, and cardiovascular risk factors. This association did not differ by HIV serostatus and persisted when excluding MWH who were not virally suppressed. Less subcutaneous adipose tissue was associated with higher odds of diastolic dysfunction. Other adipose depots were not associated with diastolic dysfunction. CONCLUSION: Greater epicardial adipose tissue and less subcutaneous adipose tissue were associated with diastolic dysfunction, regardless of HIV serostatus and viral suppression. Greater epicardial adipose tissue and less subcutaneous adipose tissue observed among PWH may contribute to risk for heart failure with preserved ejection fraction in this population.