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Background/Objectives: Antimicrobial resistance and bacterial persistence underscore the need to develop new chemotypes with multifunctional antibacterial mechanisms. This study aimed to design, synthesize, and evaluate curcumin-inspired 3,5-diarylidene-4-piperidones as versatile small molecules exhibiting antibacterial, antibiofilm, anti-efflux, DNA gyrase-inhibitory, and antiproliferative properties. Methods: A targeted series of triazole-conjugated 3,5-diarylidene-4-piperidones was synthesized through copper-catalyzed azide-alkyne cycloaddition click chemistry and subsequently characterized using standard spectroscopic techniques. The compounds were assessed for antibacterial activity against Staphylococcus aureus, Enterococcus faecalis, and Escherichia coli. Selected active compounds underwent further evaluation for DNA gyrase inhibition, antibiofilm activity against multidrug-resistant S. aureus ATCC 33591, ethidium bromide accumulation, and antiproliferative effects on HCT116 and MCF7 cancer cells, with RPE1 cells serving as a control to evaluate cytotoxicity in normal cells. Additionally, computational studies, including QSAR analysis and molecular docking, were conducted to bolster structure-activity relationships and provide mechanistic insights. Results: Several derivatives demonstrated selective antibacterial activity against Gram-positive bacteria, particularly S. aureus, while exhibiting limited or no efficacy against E. coli. Compounds 7n and 7l emerged as the most potent against S. aureus, with minimum inhibitory concentrations (MICs) of 7.8 and 8.2 μM, respectively. Notably, compound 7l inhibited S. aureus DNA gyrase supercoiling, displaying an IC50 of 3.20 μM, comparable to ciprofloxacin. Compound 7e exhibited the strongest antibiofilm activity against multidrug-resistant S. aureus, whereas compound 7a resulted in the highest accumulation of ethidium bromide, indicating robust anti-efflux activity. Antiproliferative assays revealed that select halogenated derivatives were effective against HCT116 and MCF7 cells, while the most promising antibacterial compounds exhibited minimal cytotoxicity toward RPE1 cells. Quantitative structure-activity relationship (QSAR) and docking studies supported the observed structure-activity relationships and suggested potential interactions with the ATPase binding site of DNA gyrase B. Conclusions: Triazole-conjugated 3,5-diarylidene-4-piperidones are promising multifunctional scaffolds with selective anti-S. aureus activity, antibiofilm and anti-efflux properties, and, for compound 7l, potent DNA gyrase inhibition. These findings support further optimization of this chemotype as a platform for developing antibacterial agents with polymechanistic activity.

Exercise offers many benefits, but its role in ketone body (KB) metabolism is unclear in children. Aerobic exercise enhances KB uptake into muscle and improves mitochondrial function. Reduced ketone body concentration may indicate improved mitochondrial function. We hypothesized that physical activity would reduce circulating ketone levels in children. Healthy young Black girls (n = 201) were randomized to a control condition or a daily, after-school exercise intervention. Participants (n = 53) with missing blood samples at baseline or follow up were excluded, 148 (75 intervention and 73 control) participants analyzed. The intervention entailed 30 min of homework time and 80 min of physical activity, including 35 min of moderate to vigorous physical activity over 10 months. Circulating ketone concentration was measured using nuclear magnetic resonance spectroscopy (NMR) and maximal oxygen consumption (VO2 max) assessed oxidative capacity. Participants had a mean age of 9.5 years and BMI percentile of 69.9 at baseline. After adjusting for age, BMI percentile and breast development, decreased circulating ketone levels (mean = 248-170 μM, 31.3% change, Cohen's D = 0.402, p = 0.017) were observed in the treatment group. Exercise reduces KB levels in young girls, highlighting metabolic adaptation to physical activity programming in children consistent with improved mitochondrial function. Existing literature does not consider the effects of long-term exercise on basal ketone concentration. Exercise intervention decreased serum ketone body concentration in girls. This is evidence for changes in nutrient utilization with exercise in active children. Puberty does not impact basal ketone utilization This change could serve as indication of changes in mitochondrial function.

Phenotypic modulation of vascular smooth muscle cells (VSMCs) is a hallmark of vascular remodeling and cardiovascular disease. Recent lineage-tracing and single-cell transcriptomic studies have identified secreted phosphoprotein 1 (SPP1) as a prominent marker associated with disease-associated VSMC states, particularly those linked to fibrotic remodeling and vascular calcification. However, the cellular origins and fate of SPP1-associated VSMC populations remain incompletely understood. We generated a novel Spp1-rSTOPr-Cre (Spp1Cre) knock-in mouse line in which Cre recombinase is expressed from the endogenous Spp1 locus following Dre-mediated excision of a rox-flanked transcriptional STOP cassette. Correct targeting of the knock-in allele was validated by internal, 5' junction, 3' junction, and long-range PCR analyses, as well as Sanger sequencing. To establish an intersectional lineage-tracing strategy, Spp1Cre mice were crossed with Myh11DreERT2 and Rosa26-RSR-LSL-tdTomato-LSL-eGFP reporter mice, enabling permanent labeling of VSMC-derived populations following activation of the endogenous Spp1 locus. Under physiological conditions, GFP-positive cells were detected at low frequency within the vascular wall and were predominantly negative for the contractile markers ACTA2 and MYH11. As a proof-of-principle application, GFP-positive cells markedly expanded within atherosclerotic lesions induced by PCSK9-AAV and high-fat diet feeding. These lineage-traced cells remained largely ACTA2- and MYH11-negative, consistent with a modulated phenotype. Notably, only a minority of GFP-positive cells expressed SPP1 or fibronectin at the time of analysis, demonstrating the utility of permanent lineage tracing for tracking cells with a history of endogenous Spp1 activation during vascular remodeling. We report the generation and validation of a novel Myh11Dre-Spp1Cre intersectional mouse model for lineage tracing of VSMC-derived populations that have activated the endogenous Spp1 locus. This genetic resource provides a valuable platform for investigating the origin, fate, and phenotypic evolution of Spp1-associated VSMC populations during vascular remodeling and cardiovascular disease.

Pax6 is a critical transcription factor that regulates the development of multiple tissues, including the nervous system, ocular tissues, and pancreas. We have previously demonstrated that p32 Pax6 function is substantially regulated by protein sumoylation mediated through SUMO1 at the primary residue, Lys-91, and to a less degree at Lys-110 of the p32 Pax6 (K91/110) (Yan et al., 2010, PNAS). To further investigate the function of Pax6 sumoylation, we established stable PANC-1 pancreatic cancer cell line overexpressing p32 Pax6. Injection of these cells into immune-deficient mice promoted much enhanced tumor development than both parental and vector-transfected cells. Inhibition of Pax6 sumoylation with the sumoylation inhibitor ML-792 markedly suppressed tumor growth. Moreover, ML-792 treatment of the developed tumors also significantly suppressed tumor growth. To further study the underlying mechanisms, we generated the PANC-1 cell lines expressing K91/110R-p32 Pax6 and demonstrated that inhibition of Pax6 sumoylation through K91/110R mutations also suppressed its ability to promote tumor development in nude mice. Furthermore, K91R-p32 Pax6 knock-in mice exhibited changed cell populations in adult pancreas tissue and altered transcriptomes in the pancreas in vivo, which resembled the changes observed in PANC-1 cells expressing K91/110R-p32 Pax6 ex vivo. RNA sequencing, gel mobility shifting, chromatin immunoprecipitation, and Cut & Run assays revealed that the CXXC finger protein 4 (CXXC4) is the major downstream target directly regulated by Pax6. Silencing of CXXC4 in PANC-1 and CAPAN-1 cells expressing p32 Pax6 inhibited Pax6-induced tumor development in nude mice, exhibiting the phenotype similar to that observed in PANC-1 and CAPAN-1 cells expressing K91/110R-p32 Pax6. Together, our results demonstrated that inhibition of Pax6 sumoylation suppresses tumorigenicity of PANC-1 and CAPAN-1 pancreatic cancer cells through CXXC4. Our findings suggest that targeting Pax6 sumoylation may serve as a potential therapeutic target for pancreatic cancer treatment.

Retinopathy of prematurity (ROP)-associated vision loss is driven by pathological retinal angiogenesis. Current therapies suppress neovascularization but do not fully restore vascular integrity or prevent long-term visual deficit. Activation of the sigma-1 receptor (Sig1R) has been reported to confer neuroprotection, yet its role in retinal vascular protection remains largely unexplored. Here, we investigated whether Sig1R activation confers vascular protection in experimental ROP. The oxygen-induced retinopathy (OIR) mouse model was induced in wild-type and Sig1R-/- mice with or without systemic (+)-pentazocine ([+]-PTZ) administration to activate Sig1R. Retinal vascular pathology, barrier integrity, and avascular areas were evaluated by fluorescein angiography and retinal flatmount analysis. Molecular changes in metabolic, oxidative, and inflammatory pathways were assessed by immunostaining/blotting and ELISA assay. Sig1R expression was reduced in OIR retinas, accompanied by decreased cullin-3 ubiquitin ligase (Cul3) and phosphorylated AMP-activated protein kinase (pAMPK) and increased pAkt and endothelial nitric oxide synthase (eNOS), indicative of metabolic and endothelial stress. Activation of Sig1R with (+)-PTZ restored Sig1R, Cul3, and pAMPK levels, suppressed pAkt/eNOS signaling, reduced oxidative stress, and attenuated Müller glial activation. OIR-induced upregulation of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and pro-angiogenic/inflammatory mediators, including vascular endothelial growth factor (VEGF), IL-6, TNF-α, macrophage colony-stimulating factor (M-CSF), vascular cell adhesion molecule 1 (VCAM-1), and tumor necrosis factor receptor (TNFR), were markedly reduced by (+)-PTZ. Functionally, Sig1R activation improved retinal vascular barrier integrity, reduced arterial tortuosity and pathological neovascularization, and promoted revascularization of avascular retina. Importantly, (+)-PTZ treatment failed to confer any vascular benefit in Sig1R-/- mice, confirming that these vascular benefits are Sig1R dependent. Sig1R activation preserves vascular integrity and suppresses pathological angiogenesis in OIR. Together with known neuroprotective effects, Sig1R represents a promising dual neurovascular therapeutic target for ROP.

ATP synthase inhibitory factor 1 (ATPIF1) is a critical regulator of the activity of F1F0-ATPase, a central enzyme in mitochondrial ATP production. Accumulating evidence highlights ATPIF1 as a master modulator of mitochondrial morphology, function, cellular metabolism, and stress responses in diverse physiological and pathological conditions. In this review, we first provide a brief overview of mitochondrial structure and ATP production. We then focus on the cellular and molecular mechanisms of mitochondrial bioenergetics regulated by ATPIF1 and emphasize the role of ATPIF1 in energy preservation, mitophagy and redox balance. Furthermore, we comprehensively summarize recent advances about the pathological function of ATPIF1 in various mitochondrial dysfunction related diseases, including ischemia/reperfusion injury, aging, cancer, sepsis and chronic inflammation, and neurodegenerative disorders. ATP1IF1, the mitochondrial rheostat, emerges as a novel therapeutic target to combat mitochondrial dysfunction across multiple organ systems.

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Our objective was to examine the association between mid-pregnancy leptin concentration and preeclampsia risk, adjusting for maternal risk factors. We studied 1504 women with singleton pregnancies in the Project Viva cohort. The exposure was mid-pregnancy plasma leptin concentration (mean gestational age 28 weeks), categorized into tertiles. The primary outcome was preeclampsia during that pregnancy. The secondary outcome was self-reported preeclampsia during subsequent pregnancies. We used multivariable logistic regression to assess the association of leptin tertiles with preeclampsia, adjusting for pre-pregnancy BMI, first trimester gestational weight gain, history of hypertension, age, and parity. There were two (0.4%) cases of preeclampsia among participants in the lowest leptin tertile, 20 (4.0%) in the middle tertile, and 29 (5.8%) in the highest tertile. Higher leptin levels were associated with higher odds of preeclampsia after adjustment for confounders. Compared to the lowest tertile, odds ratios were 7.5 (95% CI 1.7, 32.7) for the middle tertile and 7.0 (95% CI 1.5, 31.9) for the highest tertile. Higher leptin levels were also associated with higher odds of preeclampsia in subsequent pregnancies (6.1% vs 0.9% in the middle vs. lowest tertile, OR 6.4, 95% CI 0.7, 57.0), although the estimates were highly imprecise due to the small sample size. Higher mid-pregnancy leptin concentrations were associated with increased risk of preeclampsia, independent of maternal age, pre-pregnancy BMI, first trimester gestational weight gain, history of hypertension, and parity. Additionally, our results suggest that elevated leptin during a prior pregnancy may increase preeclampsia risk in subsequent pregnancies.

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Hair follicles, the organs that produce hair, go through a constant cycle composed of phases of growth, regression, and rest. During this cycle, matrix keratinocytes (MKs), the cells responsible for hair fiber synthesis, proliferate for several years and then undergo spontaneous apoptosis. Damage to MKs and perturbations in their normal dynamics result in a shortened growth phase of the hair cycle, leading to hair loss. The most common factors causing such disruption are hormonal imbalance and attacks by the immune system. Androgenetic alopecia (AGA) is a form of hair loss caused by high sensitivity to androgens, and alopecia areata (AA) is a condition where hair loss is caused by an autoimmune reaction against MKs. In this study, we inform a mathematical model for the human hair cycle with experimental data for the lengths of hair cycle phases available from male control subjects and subjects with AGA. We also connect a mathematical model for AA with estimates for the duration of hair cycle phases obtained from the literature. Subsequently, with each model we perform parameter screening, uncertainty quantification, and global sensitivity analysis, and we compare the results across control, AGA, and AA conditions. The findings reveal that, in AGA subjects, there is greater uncertainty associated with the duration of hair growth than in control subjects. Additionally, compared to control and AGA conditions, in AA it is more certain that longer hair growth phase could not be expected. The global sensitivity analysis results show that, in AGA conditions, synthesis of regulatory molecules in the dermal papilla and stem cell input to the MK population have high impact on hair growth duration, which agrees with physiological understanding for the effect of androgens on hair follicles in AGA.

We present a unique case of spontaneous chordal rupture in a young infant with Down syndrome and unrepaired transitional atrioventricular septal defect. This resulted in abrupt onset of severe left atrioventricular valve regurgitation, cardiogenic shock, and multiorgan dysfunction. Our case highlights the need for a high index of suspicion for a ruptured chord in a young infant presenting with acute onset of pulmonary edema.

Insomnia is common in the clinical course of schizophrenia, including in individuals at clinical high risk for psychosis (CHR-P). We previously found associations between insomnia and psychosis-risk symptoms in CHR-P. We attempted to replicate findings in an independent cohort. We explored associations between insomnia and psychosis-risk symptoms in CHR-P individuals in the Accelerating Medicines Partnership Schizophrenia (AMP SCZ) program (n = 269). We investigated relationships between insomnia and psychosis-risk symptoms (Brief Psychiatric Rating Scale [BPRS]). The prevalence of any terminal and initial insomnia at AMP SCZ baseline was 28% and 38%, respectively. After controlling for potential confounders, insomnia was a significant indicator of higher BPRS total (β = 0.33) and positive (β = 0.22), affect (β = 0.34), and activation (β = 0.13) subscale scores. Insomnia is prevalent and associated with psychosis-risk symptoms in CHR-P individuals. Findings are clinically relevant and highlight the need for more rigorous assessment and treatment of insomnia in this population.

Brain-derived neurotrophic factor (BDNF) is a key member of the neurotrophin family that promotes neuronal function via its receptor kinase TrkB. However, recent work has demonstrated BDNF as a multifaceted regulator beyond its classic roles in the nervous system, particularly in renal patho-physiology. This review summarizes the recent advances about BDNF/TrkB signaling pathway in various kidney diseases, including chronic kidney disease (CKD) and acute kidney injury (AKI). Upon binding TrkB, BDNF initiates specific intracellular signaling pathways, such as PI3K-Akt, MAPK-ERK, and PLCγ, to support cell survival, mitochondrial function, cytoskeletal integrity, and anti-inflammatory responses. As such, the BDNF-TrkB pathway represents a potential target for renal protection and regeneration, warranting further mechanistic and clinical investigation.

Many patients with chronic myeloid leukemia (CML) treated with adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) experience persistent adverse events (AEs) that negatively impact daily living and the ability to remain on treatment. Asciminib, an allosteric inhibitor of BCR::ABL1, was designed to enhance efficacy and reduce off-target effects vs ATPcompetitive TKIs. The phase 3 randomized ASC4FIRST trial established the overall favorable safety profile of asciminib in patients with newly diagnosed CML in chronic phase (CP). This exploratory post hoc analysis of ASC4FIRST focused specifically on the tolerability of asciminib vs imatinib and asciminib vs second-generation [2G] TKIs. Analyses were conducted within each stratum to account for differences between strata; patients prerandomized to the imatinib stratum were older and had higher cardiovascular risk than those in the 2G stratum. Within both strata, patients receiving asciminib experienced fewer difficult-to-tolerate AEs (such as gastrointestinal toxicity, rash, and pleural effusion) and fewer AEs leading to dose modifications and discontinuations due to nonhematologic and hematologic AEs vs the investigator-selected (IS) TKI comparator, with a shorter median duration of dose modification. Additionally, median onset of AEs leading to dose modification occurred later in patients receiving asciminib vs ISTKIs. The safety and tolerability of asciminib observed in the ASC4FIRST trial demonstrate asciminib's excellent benefit-risk profile as a frontline therapy for a broad range of patients with newly diagnosed CML-CP.

Examining nursing home staffing trends throughout COVID-19 provides critical insights for developing equitable workforce policies and resource allocation strategies. To examine differences in nurse staffing levels across community distress levels, focusing on the temporal trends from 2019 to 2023. This longitudinal observational study used random intercept mixed-effects models to analyze retrospectively collected data from 15,042 certified nursing homes. Data were merged from 2019 to 2023 Nursing Home Compare, 2019 to 2021 LTCFocus, and the 2016 to 2018 Distressed Community Index (DCI). Outcomes were case-mix adjusted hours per resident day (HPRD) for registered nurses (RNs), licensed practical nurses (LPNs), and certified nursing assistants (CNAs). Predictors included DCI quintile and calendar quarter interactions, adjusting for bed count, ownership, chain affiliation, dementia unit status, payer mix, and five-star rating. RN HPRD were lower in nursing homes in more distressed communities, with the fifth and first quintile HPRD gap widening during the pandemic (2020 Q2 = -0.187 [-0.220, -0.155]; 2020 Q3 = -0.201 [-0.234, -0.169]; 2020 Q4 = -0.211 [-0.244, -0.179]). LPN HPRD were highest in the most distressed communities, with the fifth and first quintile gap narrowing post-pandemic (2021 Q4 = 0.050 [0.022, 0.077]; 2022 Q4 = 0.036 [0.009, 0.063]; 2023 Q4 = 0.027 [0.000, 0.054]). CNA HPRD were lowest in the most distressed communities and varied inconsistently across communities, with post-pandemic levels falling below pre-pandemic baselines. The pandemic widened RN staffing gaps in distressed nursing homes, forcing LPN substitution, while CNA staffing fell below pre-pandemic levels. Addressing these compounding shortages requires targeted financial incentives and equitable, data-driven staffing policies. Distinct staffing patterns across DCI quintiles call for systematic investigation into appropriate staffing levels and targeted policies to ensure quality care in under-resourced nursing homes and inform public health emergency preparedness.

Mitral annular disjunction (MAD) is increasingly recognized as a structural abnormality associated with ventricular arrhythmias and sudden cardiac arrest, particularly in the setting of bileaflet mitral valve prolapse (MVP). A 43-year-old man with a history of migraines presented following a witnessed out-of-hospital cardiac arrest and was successfully resuscitated with a single AED shock. Transthoracic echocardiography showed mitral regurgitation with bileaflet prolapse and suspected MAD. An implantable cardioverter-defibrillator was placed for secondary prevention, and the patient was discharged in stable condition with outpatient surgical follow-up where robotic-assisted mitral valve repair was successfully performed. Advanced imaging plays a pivotal role in diagnosis and risk stratification when MAD presents as sudden cardiac arrest.

Alzheimer's disease is more prevalent among females. Estrogens influence brain metabolism and function, and low blood levels before, during, and after menopause may be associated with cognitive decline in later years. Here, we investigate the association between hormone therapy and reproductive lifespan with cognitive performance using a nationally representative sample from the National Health and Nutrition Examination Survey (NHANES) database. This cross-sectional study included 1,374 eligible women aged 60 years or older from the NHANES database. Cognitive performance was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) word learning subtest, the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). Univariate analysis and multivariate logistic regression were employed to evaluate the association between hormone therapy, reproductive span, and cognitive performance. Restricted cubic spline curves were used to assess the relationship between age as a continuous variable and cognitive performance. After adjusting for age, race, and educational level, hormone therapy was significantly associated with word recall, digit symbol, and animal fluency cognitive performance (p < 0.05). The reproductive span was associated with word recall performance (p = 0.027) but not with digit symbol or animal fluency. The age-related cognitive decline is attenuated by hormone therapy with maximum effect between 65 and 70 years for all dimensions. There is a positive association between hormone therapy and cognitive performance in postmenopausal women, particularly in age groups with the steeper decline. In addition, there is no significant association between reproductive span and cognitive function.

Chronic tumor-associated inflammation can impair dendritic-cell (DC) antigen presentation and limit immune engagement, posing a barrier to ferroptosis-based therapeutic strategies that often intensify oxidative stress. Here we develop an inflammation-compatible ferroptosis-inducing therapeutic platform by co-integrating an NF-&#x3ba;B-modulating small molecule, celastrol, with an iron-coordinated mesoporous polydopamine carrier (mPDA-Fe-Cel). The platform combines 808-nm photothermal heating with iron redox cycling to promote lipid peroxidation, while concurrently attenuating inflammatory signaling programs, thereby supporting ferroptosis-associated tumor cell damage in a more immune-permissive context. In tumor cells, mPDA-Fe-Cel increases labile Fe&#xb2;&#x207a;, depletes glutathione, downregulates GPX4, and amplifies lipid peroxidation, consistent with ferroptosis-associated cell death and accompanied by immunogenic cell death hallmarks, including calreticulin exposure, HMGB1 release, and ATP secretion. In parallel, transcriptomic and protein-level analyses indicate attenuation of NF-&#x3ba;B-linked inflammatory programs, with prominent suppression of a CXCL8-centered signature, together with reduced activation of Toll-like receptor and NOD-like receptor pathways. Functionally, tumor-conditioned cues generated by the nanoplatform support DC maturation and antigen-presentation-related phenotypes (MHC-I/MHC-II and costimulatory markers), coinciding with enhanced intratumoral CD8&#x207a; T-cell infiltration and improved antitumor efficacy in murine models with favorable biosafety. Collectively, this work outlines a materials-based strategy that couples ferroptosis induction with inflammatory modulation to facilitate immune-compatible cancer nanotherapy.