Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with significant involvement of neuroinflammation, for which the current interventions are limited in efficacy. Certain antihistamines such as clemastine have neuroprotective properties beyond H1 receptor antagonism, including anti-inflammatory, antioxidant, remyelinating effects, modulates neuroinflammatory pathways. This study aims to investigate the neuroprotective potential of clemastine via in silico and in vivo studies for repurposing against AD. In silico analyses involved network pharmacology, molecular docking, and 100-ns molecular dynamic simulations along with principal component analysis and binding free energy calculations. Whereas, experimental studies involved treatment of clemastine (5 mg/kg and 10 mg/Kg, p.o.) for 14 days in lipopolysaccharide-induced neuroinflammatory (250 µg/Kg, i.p.) rat. Behavioral assessment was performed using Morris water maze (MWM) test. Biochemical parameters including acetylcholinesterase (AChE) activity, oxidative stress markers (MDA, SOD, CAT, GSH), and inflammatory biomarkers (NLRP3, TNF-α, IL-1β) were evaluated. Histopathological analysis of hippocampal CA3 region was performed using Nissl's staining. Network analysis identified 52 overlapped targets between clemastine and AD. Hub genes such as GSK3β, DRD1, DRD2, CHRNA4, and SLC6A4 were associated with neurotransmission and kinase signaling pathways. Enrichment analysis highlighted PI3K/Akt, MAPK, and neuroactive ligand-receptor interaction pathways. Molecular docking and molecular dynamic simulations confirmed stable binding of clemastine with GSK-3β, PI3K, and NLRP3 proteins. Animal model studies demonstrated that clemastine significantly improved cognitive performance in MWM (p < 0.001), reduced AChE level (p < 0.0001), restored antioxidant enzyme levels, suppressed inflammatory mediators (p < 0.0001), and preserved hippocampal neuronal structure. The study provides novel integrative evidence linking its antihistaminic action with simultaneous regulation of neuroinflammation through multi-target modulation of inflammation, oxidative stress, and neuronal signaling pathways, highlighting its potential as a promising repurposed therapeutic candidate for AD.
Macroautophagy (autophagy) enables cellular stress adaptation by degrading damaged components; ULK1, a serine/threonine kinase, initiates this process in response to nutrient and energy cues. While autophagy is well studied, few investigations have directly tested ULK1 in cancer progression. Emerging functional data across numerous cancers indicate that ULK1 can promote or restrain malignant behavior through both autophagy-dependent and autophagy-independent mechanisms, modulating mitochondrial quality, anoikis escape, invasion, therapy adaptation, and immune visibility. Pharmacology has advanced from early ULK1/2 inhibitors to structure-guided and machine learning-derived inhibitors with improved potency and selectivity. The first clinical agent, DCC-3116, demonstrates on-target engagement with acceptable tolerability and is being evaluated in combinations where therapy induces autophagy. Here, we review ULK1 as a regulator of cancer progression, synthesizing pan-cancer clinical and functional evidence alongside the evolving pharmacology of ULK1 modulation to define the settings in which its targeted inhibition may be most effectively translated.
Previous studies suggest endogenous ovarian hormones significantly increase binge-eating (BE) risk in females. Approximately 85% of women use combined oral contraceptives (COCs) that mimic the riskiest hormonal milieu for BE (ie, elevated estradiol and progesterone postovulation). The effects of COCs on BE risk remain unknown. To examine the associations of COCs with BE. This population-based longitudinal survey study collected daily reports of COC active vs inactive pill use and BE across 49 consecutive days in women from the Michigan State University Twin Registry. Analyses examined within-person changes in a continuous measure of BE (ie, emotional eating [EE]) when women were using active hormone pills vs inactive pills. Data were collected from 2017 to 2024. Participants were women already using monophasic COCs. Analyses examined the full sample as well as women with clinically defined BE episodes. Data were analyzed from April 2024 to November 2025. COC pill type (active vs inactive pills). The outcome of interest was within-person changes in EE between inactive vs active hormone pills, controlling for negative affect. Changes across 2 pill packs were examined for replication. Analyses also examined weight preoccupation (WP) as a control outcome, given its lack of past associations with ovarian hormones. Primary models focused on the full sample; sensitivity analyses examined women with clinically defined BE. A total of 422 women (mean [SD] age, 21.95 [3.10] years) were included in the full sample. Significant within-person increases in EE were observed in the full sample during active hormone vs inactive pills in both cycles (cycle 1: β = 0.11 [95% CI, 0.06 to 0.16]; cycle 2: β = 0.07 [95% CI, 0.04 to 0.10]). Increases were not mediated by changes in negative affect and were observed in the subsample of 51 women (mean [SD] age, 22.44 [3.57] years) with clinically defined BE episodes (cycle 1: β = 0.13 [95% CI, -0.07 to 0.33]; cycle 2: β = 0.12 [95% CI, 0.02 to 0.23]. Importantly, no significant changes in WP were observed across pill type, and post hoc analyses of negative affect as the outcome showed more modest COC outcomes. This intensive, daily survey study of COC use found a specific association of active COC pills with risk for EE. Future studies are needed to identify for whom COCs are most risky to inform personalized medicine and identify contraceptive options that may be less likely to impact BE or EE.
To assess the effect of maternal oil spill exposure on children's mental health and examine whether maternal resource loss mediated this relationship. 445 mother-child pairs from the Women and Their Children's Health Study in Louisiana (2012-2016) were examined. Maternal oil spill exposure from the 2010 Deepwater Horizon Oil Spill was measured at Wave 1 (2012-2014), while children's mental health and maternal resource loss were assessed at Wave 2 (2014-2016). Structural equation modeling estimated the direct and indirect effects of maternal oil spill exposure on children's mental health through maternal resource loss. Mothers (mean age 42 years (SD 7.7) and children (mean age 13 years (SD 2.2)) were interviewed. Maternal oil spill exposure was not directly related to children's mental health (est = -0.08, p = 0.436). However, exposure was associated with increased maternal resource loss (est = 0.45, p < .0001), which was associated with worse children's mental health (est = 0.27, p < .0001). Maternal oil spill exposure was compatible with an indirect negative effect on children's mental health (i.e., worse mental health scores) mediated by resource loss (est = 0.12, p < 0.005). Findings suggest maternal oil spill exposure indirectly affects children's mental health through resource loss. Interventions mitigating resource loss are vital for supporting children's mental well-being after disasters.
Reliable population pharmacokinetic (PopPK) estimation is often compromised by outliers under Gaussian error models. While post hoc filtering using conditional weighted residuals (CWRES) is common, this approach is often insensitive due to model "masking" from variance inflation. We implemented a one-compartment model in Monolix using a custom likelihood workaround to benchmark four distributions: Normal, Laplace, Generalized Error Distribution (GED), and Student's t. We assessed CWRES sensitivity under extreme contamination and compared estimation performance using theoretical tail-behavior analysis, controlled simulation studies spanning multiple contamination severities, and a real-world caffeine PK case study with influential terminal-phase deviations. Simulations revealed that CWRES-based diagnostics are unreliable; extreme outliers frequently produced |CWRES| < 6 because the Normal model inflated residual variance, masking the contamination. Exponential-tail models (Laplace, GED) improved robustness for moderate outliers but failed under extreme deviations due to insufficiently heavy tails. Conversely, the Student's t model, utilizing power-law tail behavior, maintained stable and minimally biased structural parameter estimates across the contamination settings examined. These patterns were confirmed in the caffeine case study. Reliance on CWRES-driven residual screening alone is methodologically fragile. Among the models evaluated, exponential-tail distributions are insufficient for extreme outliers, whereas the Student's t distribution provided the most consistent stability across the contamination settings examined here and showed the most robust overall performance among the residual-error models evaluated when influential outliers were present.
Neisseria gonorrhoeae is a common Gram-negative pathogen with increasing resistance to all recommended antibiotics. There is a critical need to improve the efficiency of the antibiotic hit discovery process to replenish the drug development pipeline. Here, we show that deep learning models can augment high-throughput screens to identify readily available molecules with narrow-spectrum activity against difficult-to-treat strains of N. gonorrhoeae. We phenotypically tested 38,650 small molecules for N. gonorrhoeae growth inhibition to train a predictive graph neural network (GNN) model. We benchmarked the model's performance against other architectures, including a large language model, and found that GNNs more accurately identify active, drug-like molecules that are structurally distinct from the training set and known antibiotics. Using the model to virtually screen ~6 million compounds, we identified 213 compounds for experimental validation and found that 83 (39%) inhibited N. gonorrhoeae growth. Two of these compounds were structurally dissimilar to existing antibiotics, maintained potency against multidrug-resistant N. gonorrhoeae strains in vitro, exhibited promising selectivity indices, and were rapidly bactericidal with low frequencies of resistance. Proteomic studies revealed their distinct mechanisms of action, with one compound targeting alanine racemase, an enzyme involved in the essential process of peptidoglycan synthesis. Furthermore, the compounds showed early promise in reducing N. gonorrhoeae titers in a human vagina-on-a-chip infection model and a mouse vaginal infection model. Our work establishes the deep learning-enabled discovery of selective antibacterial compounds against N. gonorrhoeae as a much-needed hit discovery tool to address the growing crisis of antimicrobial resistance for this pathogen.
In Alzheimer's disease (AD), senescent astrocytes fuel neuroinflammation and neuronal damage via the senescence-associated secretory phenotype (SASP). Calcium signaling plays a crucial role in this process, but the underlying molecular mechanisms remain elusive. We retrieved scRNA-seq data from the Gene Expression Omnibus (GEO) for AD and control brains. After cell-type annotation, we resolved astrocyte sub-clusters. Pseudotime trajectory and differential-expression analyses identified SORBS1 as a key senescence-related gene, which we followed with gene-set enrichment analysis. Next, we established an in vitro AD model by treating astrocytes with amyloid-β (Aβ). We evaluated astrocyte senescence using SA-β-gal staining, qRT-PCR, Western blot (WB) for senescence markers, and ELISA for SASP cytokines. We measured concentration of Ca2+ with Fluo-4 AM probes. Subsequently, bioinformatic screening predicted FBXO22 as an interactor of SORBS1 and BAG3 as a ubiquitination substrate of FBXO22. We validated these interactions using Co-IP and in vitro ubiquitination assays. Finally, we constructed an astrocyte-neuron co-culture model. We detected neuronal cell viability, AChE activity, AD phenotype-related protein expression, apoptosis, and levels of inflammatory factors using MTT assay, specific kits, WB, flow cytometry, and ELISA, respectively, to assess neuronal damage. ScRNA-seq analysis revealed a marked reduction in astrocyte expression in AD brains, which may result from cellular senescence. The SASP gene SORBS1 was selectively up-regulated in astrocytes and significantly enriched in calcium-signaling pathways. Functional assays confirmed that SORBS1 accelerated astrocyte senescence. Mechanistically, SORBS1 interacted with FBXO22 to promote the ubiquitin-dependent degradation of BAG3, thereby amplifying calcium signaling, accelerating astrocyte senescence, and contributing to AD-related neuronal damage. We uncover a novel mechanism by which the SORBS1/FBXO22/BAG3 axis drives astrocyte senescence through the regulation of calcium signaling, thereby influencing AD-related neuronal damage. This finding provides a potential therapeutic target for AD treatment by targeting astrocyte senescence.
This study investigated the antioxidant properties and enzyme-inhibitory activities of Cousinia cirsioides extracts and sub-extracts, along with their phytochemical composition. In this study, the aerial parts of C. cirsioides were extracted with 70% methanol and fractionated into n-hexane, ethyl acetate (CSE), n-butanol, and water sub-extracts. Enzyme inhibition activities were tested against α-amylase, α-glucosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and tyrosinase. Antioxidant capacities were evaluated using DPPH, ABTS, FRAP, and CUPRAC assays. TPC, TFC and LC-HRMS analyses were used to identify the phytochemical profile of the extracts. Additionally, the antimicrobial activity was investigated using the microdilution method. As a result, the CSE sub-extract exhibited the most potent antioxidant and enzyme inhibitory activities among the extracts. It showed significant inhibition of α-amylase (IC50 = 167.967 µg/mL), AChE (IC50 = 134.165 µg/mL), and tyrosinase (IC50 = 122.354 µg/mL), among others. Moreover, a moderate antimicrobial effect was found in n-hexane sub-extract. LC-HRMS analysis revealed high levels of isoquercitrin, caffeic acid, chlorogenic acid, and protocatechuic acid in the active sub-extract. These compounds were also subjected to the same bioactivity tests. It is revealed that these compounds demonstrated individual bioactivities, although less potent than the extract, suggesting synergistic effects.
Serum uric acid (SUA) and hyperuricemia have re-emerged as determinants of cardiovascular (CV) risk beyond gout. This review integrates epidemiological, Mendelian randomization (MR), and pharmacological evidence to define the role of SUA and urate-lowering therapy (ULT) in contemporary cardiovascular pharmacotherapy. We synthesized population-based studies, MR and drug-target MR analyses, and randomized trials of xanthine oxidase inhibitors (XOIs), uricosurics/URAT1 inhibitors, biologic uricases, and CV drugs with urate-modifying effects. Hyperuricemia is prevalent and rising, often closely accompanying obesity, hypertension, diabetes, and chronic kidney disease. Higher SUA correlates with coronary artery disease, heart failure, stroke, cardio-renal-metabolic syndromes, and mortality, with non-linear risk relationships and sex- and age-specific thresholds. MR suggests a modest causal contribution of genetically elevated SUA to blood pressure, coronary disease, and advanced CKD, partly mediated via haemodynamic, renal, and inflammatory pathways. Pharmacologically, XOIs, URAT1 inhibitors, and uricases differ in kinetics and safety profiles. However, large trials and real-world cohorts show no consistent reduction in CV events when ULT is added to guideline-directed therapy in asymptomatic hyperuricemia, stable ischaemic heart disease, chronic heart failure, or chronic kidney disease. Observational data suggest that long-term, adequately dosed XOIs and high cumulative uricosuric exposure may reduce coronary risk. SUA is a cardio-renal-metabolic biomarker and a plausible therapeutic target in selected cardio-renal-metabolic phenotypes. However, evidence does not support routine ULT for CV prevention in asymptomatic hyperuricemia. ULT should remain focused on gout and symptomatic hyperuricemia, with phenotype-guided strategies to identify patients most likely to benefit.
Hypothermia and hypometabolism are important for hibernating animals to survive harsh environmental conditions. Induction of a hypothermic and hypometabolic state is considered an avenue to treat severe diseases, such as ischemic stroke. However, noninvasive and safe methods to achieve a long-lasting hypothermic and hypometabolic state remain limited. Here, we present data from preclinical and clinical studies to explore the feasibility and safety of drug-induced hypothermia by administration of chlorpromazine and promethazine (C+P). In mice, C+P treatment induced hypothermia and suppressed glucose metabolism in the brain. C+P treatment reduced infarct volumes and improved neurological deficit in a mouse middle cerebral artery occlusion model induced by suture insertion. Furthermore, C+P treatment reduced body temperature, suppressed metabolism, and exerted cerebroprotective effects in a rhesus monkey model of stroke. In a double-blind, phase 1 clinical trial (NCT06663631), a total of 32 patients diagnosed with acute ischemic stroke were enrolled, receiving either placebo or increasing doses of C+P treatment: 10, 20, 50, or 100 milligrams. All doses were safe and well tolerated. Only 100 milligrams of C+P resulted in a modest and transient reduction in body temperature. Plasma proteomic profiling revealed a down-regulation of markers associated with aerobic respiration and glucose metabolism. These findings highlight the translational potential of C+P treatment and warrant a larger trial to further investigate safety and efficacy of C+P.
Talquetamab (TAL) frequently induces a distinctive dysgeusia that diminishes eating enjoyment, oral intake, and quality of life in patients with multiple myeloma (MM). Patient-centered, evidence-based nutritional guidance tailored to TAL-related sensory phenotypes is scarce. This mixed-methods study aimed to characterize patient experiences, identify preferred dietary adaptations, and translate these findings into a proposed exploratory clinical workflow and a digital companion support concept for future validation. A prospective, single-center exploratory mixed-methods study was conducted in talquetamab-treated patients with multiple myeloma who reported new-onset taste change (n = 25). Patient-reported dysgeusia, xerostomia symptoms, dietary experiences, and coping strategies were captured using a structured questionnaire with free-text fields. Taste change and xerostomia were assessed by patient report; objective psychophysical taste testing and sialometry were not performed in this cohort. Free-text responses were analyzed by two independent coders using reflexive thematic analysis with iterative consensus. Quantitative data were summarized descriptively. Integrated findings were translated in interprofessional focus groups into two exploratory supportive-care outputs: a proposed clinical workflow and a digital companion blueprint for future validation. Patients described heterogeneous and individualized taste disturbances, including reduced or unpleasant perception of sweet flavors, bitter/sour aversions, spice-related mucosal sensitivity, and reduced enjoyment of meals. Patient-reported xerostomia symptoms aggravated intolerance to dry or fibrous foods and impaired swallowing comfort. Frequently reported coping strategies included mild herbs and aroma cues, umami-rich additions, sauce- or soup-based texture modification, temperature and plating adjustments, saliva-supportive measures, and environmental or behavioral strategies. Based on these findings, we developed an exploratory supportive-care workflow incorporating cycle-based symptom screening, prospective use of validated taste assessment where feasible, structured xerostomia and nutritional-risk assessment, phenotype-oriented dietary suggestions, safety escalation, and follow-up. A digital companion blueprint (GUSTABOR) was conceptualized to support future individualized dietary guidance after usability and effectiveness testing. Talquetamab-related dysgeusia is clinically meaningful, heterogeneous, and closely linked to oral dryness symptoms, food texture tolerance, eating enjoyment, and social participation. The proposed workflow and digital companion blueprint should be interpreted as exploratory supportive-care concepts derived from patient-reported experience, not as validated clinical tools. Prospective multicenter studies using validated taste instruments, objective salivary-flow assessment, nutritional endpoints, and implementation outcomes are required before routine clinical adoption. Structured symptom screening, validated taste assessment where feasible, and individualized nutrition support may help identify patients at risk for reduced intake, weight loss, and impaired quality of life during talquetamab therapy. Digital support could broaden access to tailored guidance, but should be implemented only after prospective evaluation of usability, safety, resource requirements, and clinical benefit.
Microplastics (MPs) are recognized as vectors for microorganisms in aquatic ecosystems, raising concerns about their environmental implications. We examine the structural and chemical properties of recycled PET microplastics and their interactions with Escherichia coli (E. coli) using Fourier-transform infrared (FTIR) and Raman spectroscopy. FTIR analysis identified nine characteristic vibrational bands of PET, and Raman spectroscopy confirmed that neither glutaraldehyde treatment nor bacterial exposure produced significant chemical changes in the PET structure. Scanning electron microscopy (SEM) and Gram staining revealed bacterial adhesion and biofilm formation on microplastic surfaces. Additionally, E. coli colonies exhibited reduced lactose fermentation activity. These findings reinforce the role of MPs as microbial vectors and demonstrate the ability of E. coli to colonize synthetic polymers. The development of rapid spectroscopic tools could enhance monitoring efforts in both laboratory and field environments. This study contributes to the growing understanding of MPs-microorganism interactions, and a model system of MPs-microorganism interaction is proposed.
The organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are hepatic transporters that mediate the uptake of numerous therapeutics like antibiotics and statins. Various post-translational modifications, eg, phosphorylation and glycosylation, have been shown to impact OATP1B1 and OATP1B3 function and localization. S-palmitoylation (also known as S-acylation or palmitoylation) is a reversible post-translational modification that adds palmitic acid (C16:0) to cysteine residues and can influence a protein's function, localization, and protein-protein interactions. In this study, we investigated and characterized palmitoylation in OATP1B1 and OATP1B3. Using site-directed mutagenesis and acyl-resin-assisted capture assays, residue Cys24 was identified as the palmitoylation site for both these proteins. Uptake function and surface biotinylation experiments demonstrated that palmitoylation does not affect the individual function and surface expression of OATP1B1 and OATP1B3. Coexpression studies revealed a decrease in OATP1B1-OATP1B3 interactions when nonpalmitoylated OATP1B1 or nonpalmitoylated OATP1B3 are coexpressed with their wild-type counterparts, suggesting that S-palmitoylation regulates protein-protein interactions between OATP1B1 and OATP1B3. SIGNIFICANCE STATEMENT: This study identified and characterized palmitoylation of the organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Both OATP1B1 and OATP1B3 can be palmitoylated on the conserved Cys24 residue. Palmitoylation of these 2 transporters does not impact their individual function or surface expression. However, the interaction between these 2 proteins is affected when their palmitoylation state is altered.
A contextual understanding of how neonatal and infant health inequities have developed is crucial to dismantle the harmful effects of race-based medicine and transition to a race-conscious, trauma-informed approach. Past and present laws and policies not only influence the socio-cultural context within which people live but also the accessibility and quality of healthcare delivered to birth people and infants. Race-based medicine, operationalizes race as a proxy for presumed biology in medical risk and treatment algorithms. Many examples of this exist within Obstetrics and Neonatal-Perinatal Medicine and have contributed to healthcare generated inequities. Transitioning to a race-conscious, trauma-informed approach requires acknowledging racism, not race, as a driver of outcome disparities and intentionally directing efforts towards mitigating and eliminating these inequities. This involves considering barriers that some families face outside of and within the Neonatal Intensive Care Unit, applying a culturally attuned and personalized approach, revising outdated policy and practice, diversifying the workforce, including key stakeholders in decision making, and improving transparency in research design and evaluation. This supplement explores the inequities that become amplified or compounded across the perinatal life continuum from birth person to infant, relevant policies or interventions to mitigate and eliminate the inequities, and associated outcomes. The perinatal, neonatal, and pediatric community must continue to critically assess policy and research, recognizing the impact of racism on health inequities, medical education, and patient care.
Cryptococcus neoformans is the leading cause of fungal meningoencephalitis. Cellular heterogeneity during cryptococcal infection contributes to host adaptation and fungal pathogenesis. C. neoformans titan cells and seed cells represent enlarged and small-sized morphotypes, respectively, which exhibit distinct transcriptional profiles and can be induced by environmental factors. In this work, we describe a distinct small morphotype of C. neoformans, referred to as ovoid cells. The formation of ovoid cells is promoted by host-related conditions such as nutrient limitation and elevated CO2 levels, which was observed during the late stage of cryptococcal infection. In addition to their smaller size compared to typical yeast cells, ovoid cells highly express OSP1, a marker distinguishes ovoid cells from other small morphotypes, including seed cells and titanides. These cells exhibit an increased budding and proliferation rate, which is consistent with transcriptome data that ovoid cells upregulate cell cycle related genes. We further demonstrate that the glucose repression signaling pathway and the cAMP/PKA pathway are involved in ovoid cell formation in C. neoformans. Ovoid cells show reduced fungal virulence but enhanced tolerance under long-term fluconazole treatment, indicating their important role in the balancing virulence and antifungal tolerance within C. neoformans populations.
Skeletal muscle function is critically dependent on the metabolism of cholesterol and its sarcolemmal levels. Decreased cholesterol availability is associated with various pathological conditions, causing muscle weakness. Here, we tested the hypothesis that a reduction in cholesterol content can affect the resting membrane potential, an essential parameter for membrane transport and electro-mechanical coupling in fibers of mouse diaphragm, the main respiratory muscle. 20-min exposure to methyl-β-cyclodextrin (MβCD) concentration-dependently reduced the level of muscle cholesterol. This effect was more pronounced in surface muscle fibers, where MβCD at a concentration of 30 mM decreased cholesterol content by 40% and depolarized the membranes by approximately 20 mV in both junctional and extrajunctional regions of the muscle fibers. MβCD-induced depolarization was inhibited by approximately 20%, 19%, 34%, and 42% with GIIIB µ-conotoxin (Nav1.4 channel inhibitor), nitrendipine (L-type Ca2+ channel blocker), A-784,168 (TRPV1 antagonist), and ruthenium red (nonselective blocker of Ca2+ channels), respectively. MβCD increased sarcoplasmic Ca2+ levels at resting conditions and interfered with sarcolemma integrity in some muscle fibers. Finally, 30 mM MβCD aggravated muscle fatigue and disrupted the recovery of the contraction force at direct stimulation. These results indicate that plasma membrane cholesterol is essential for the maintenance of resting membrane potential due to restricting the activity of Ca2+ (TRPV1, Cav1.1) and Na+ (Nav1.4) channels as well as keeping membrane integrity in skeletal muscle. Cholesterol depletion-induced membrane depolarization might be a potential reason for muscle weakness.
Gestational environmental chemical exposures are widespread. Some chemicals are known to adversely affect birth outcomes, but many remain understudied. To evaluate associations of gestational exposure to a priori identified chemicals in 10 classes with birth outcomes in a large, diverse US cohort. In the prospective Environmental influences on Child Health Outcomes Cohort study, 5318 mother-child pairs were enrolled from January 1, 2000, to December 31, 2021, with data on gestational urinary chemical concentrations, gestational age at birth, and birth weight. Statistical analysis was performed from January 2024 to February 2026. In single, midgestation (median, 25 weeks [IQR, 21-30 weeks]) urine samples, concentrations of 113 analytes (chemicals or their metabolites) from 10 chemical classes were simultaneously measured: fungicides and herbicides (n = 11), insecticides (n = 20), halogenated phenols (n = 5), organophosphate esters (n = 10), benzophenones (n = 6), bisphenols (n = 14), parabens (n = 6), antimicrobials (n = 2), phthalates or alternative plasticizers (n = 32), and polycyclic aromatic hydrocarbons (PAHs) (n = 7). Linear mixed-effects regression models with a random effect for site were used to estimate covariate-adjusted differences in gestational age at birth (days) and birth weight-for-gestational age (BW-GA) z scores per IQR increase in urinary analyte concentrations. In secondary analyses, odds ratios (ORs) for preterm birth and small for gestational age (SGA) were estimated. In the sample of 5318 mother-child pairs, most infants (2667 female [50%]; median gestational age at birth, 39.0 weeks [IQR, 38.0-40.0 weeks]) were born to college-educated (67% [3218 of 4785]), parous (56% [2815 of 5007]) mothers (median age at delivery, 30.7 years [IQR, 26.1-34.3 years]). A total of 43 of 113 analytes (38%) were detected in 50% or more of samples. Multiple phthalates or alternative plasticizers were associated with younger gestational age at birth or lower BW-GA z scores; for example, summed diisononyl phthalate metabolites were associated with a 0.6-day (95% CI, -1.0 to -0.1 days) younger gestational age (preterm birth OR, 1.16 [95% CI, 1.01-1.34]), and summed phthalate or alternative plasticizers were associated with a 0.06 (95% CI, -0.11 to -0.02) lower BW-GA z score (SGA OR, 1.09 [95% CI, 0.93-1.27]). Two halogenated phenols, benzophenone 8, bisphenol F, and several PAHs were associated with lower BW-GA z scores; for example, 1- and 9-hydroxphenanthrene were associated with a 0.04 (95% CI, -0.08 to -0.01) lower BW-GA z score (SGA OR, 1.13 [95% CI, 1.01-1.27]). This large cohort study of diverse US pregnancies found widespread exposure to 10 classes of environmental chemicals, many of which were associated with differences in gestational age at birth or lower BW-GA z scores. These findings indicate that reducing gestational exposure to chemicals, particularly phthalates or alternative plasticizers and PAHs, could promote healthy deliveries and better child outcomes.
The number of patients on hemodialysis is steadily increasing in Gulf Arab countries, including Bahrain. Such treatment modality has a negative impact on the quality of life, particularly sleep quality. This study aimed to assess the factors affecting the sleep pattern disturbances of hemodialysis patients in Bahrain. A cross-sectional design was employed. A convenience sample of 174 patients was recruited to the study from one of the main dialysis centers in Bahrain. Data was obtained via the Pittsburgh Sleep Quality Index questionnaire. Both univariate and multivariate analyses were used. A p value of less than 0.05 was considered statistically significant. Most of the patients had poor sleep patterns (91%). It would appear that the main contributing factors are older age (p=0.009), self-rated health (p=0.001), anemia (p=0.002), excessive weight gain, and pain symptoms after dialysis session (p=0.001, p=0.001 respectively) and taking medications for sleep (p=0.016). There is an extremely high level of poor sleep quality among patients on hemodialysis. The contributing factors are multifactorial. There is an urgent need to include sleep assessment, mental health screening, and psychosocial support education into the routine nephrology care program.
This study investigated the polyphenolic composition, antioxidant capacity, and antianemic effects of aqueous leaf (JPEL) and berry (JPEB) extracts of Juniperus phoenicea ssp. turbinata L. (J. phoenicea ssp. turbinata). The plant is traditionally used to treat various ailments. HPLC-DAD analysis identified quercetin as the major compound (JPEB 49.09%; JPEL 31.34%), followed by p-coumaric acid (27.07% in JPEB), catechin (14.69% in JPEL), and gallic acid (JPEB 13.69%; JPEL 12.08%). Antioxidant activity was assessed using DPPH and reducing power assays, with the most active extract showing IC50 = 23.95 ± 0.64 µg/mL and EC50 = 300 ± 1.41 µg/mL. In vivo, 25 rats were assigned to 5 groups: negative control, PHZ-induced anemic control (40 mg/kg), JPEL-treated, JPEB-treated (300 mg/kg/day for 21 days), and a positive control (ascorbic acid, 10 mg/kg/day). Both extracts significantly ameliorated PHZ-induced hematological disturbances, restoring values toward normal. Molecular docking revealed favorable binding affinities of key phytochemicals with deoxy-hemoglobin and the TRPV4 ankyrin domains, suggesting potential interactions at these targets. However, these in silico findings are predictive and do not confirm functional protection or protein stabilization. The experimental results demonstrated antioxidant activity and improvement of hematological parameters in the animal model. These findings suggest that J. phoenicea ssp. turbinata extracts may warrant further investigation as natural sources of bioactive compounds. Nevertheless, additional pharmacological, toxicological, and clinical studies are required to validate these effects and assess their relevance for therapeutic applications.
Spatial manipulation of flow gradients and chemical microenvironments is essential for understanding fundamental biological mechanisms and investigating therapeutic responses in adherent cells. Convection-dominated gradient generators in microfluidic devices enable tunable chemical and shear stress gradients across large cell culture areas. However, most concentration generators are irreversibly sealed and operate in a narrow range of shear stresses, which restricts access to the cells after treatment and the physiological relevance of the flow conditions. Here, we present a reversibly sealable microfluidic platform that enables spatiotemporally controlled delivery of multiple small molecules to mammalian cells grown on large glass coverslips. Our device generates a relatively wide range of shear stresses and robust, spatially predictable chemical gradients across centimeter-scale areas and provides optical access compatible with live-cell imaging; it operates in the Stokes and laminar flow regimes. A mechanical sandwich clamp enables leak-free perfusion into the cell culture chamber and access to the cells after treatment. We experimentally and numerically demonstrate the ability to modulate the amount of mixing between co-flowing streams of small molecules. We verify the uptake of fluorophores across a monolayer of cells and assess their viability after perfusion and removal from the device. This platform provides a versatile and reusable approach for studying cellular responses to microenvironmental gradients in varied physiologically relevant shear stress conditions.