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Integrating network toxicology, machine learning, and single-cell sequencing to reveal the FASN-mediated role of phenolic endocrine disruptors in water in promoting prostate cancer

Background Phenolic endocrine-disrupting chemicals (EDCs) like nonylphenol (NP) and octylphenol (OP) are widespread water pollutants. Their estrogen-like properties are suspected contributors to prostate cancer, but their precise molecular mechanisms remain unclear. Methods We employed a multidimensional framework to investigate this link. Potential NP/OP targets were predicted using SwissTargetPrediction, SEA, and CTD databases and cross-referenced with prostate cancer-associated genes from GeneCards and OMIM. Differential expression analysis of the GSE46602 dataset (36 tumor vs. 14 benign samples) identified candidate genes, which were refined to core genes using Least Absolute Shrinkage and Selection Operator (LASSO) and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) algorithms. Their diagnostic power was evaluated via an Artificial Neural Network (ANN) model and validated in The Cancer Genome Atlas (TCGA) cohort. Single-cell RNA sequencing data from six prostate cancer samples (GSE137829) were analyzed to reveal cell-type-specific expression patterns. Molecular docking and molecular dynamics (MD) simulations assessed binding stability between pollutants and target proteins. Results We identified 143 overlapping genes between NP/OP targets and prostate cancer-associated genes, significantly enriched in lipid metabolism and prostate cancer pathways (adjusted P < 0.05). Dual-algorithm screening identified four core genes (ENPP2, FASN, PTGS2, and CHRM1). Among them, Fatty Acid Synthase (FASN) exhibited the best diagnostic performance in the TCGA validation cohort (AUC = 0.800), outperforming PTGS2 (0.783), ENPP2 (0.621), and CHRM1 (0.605), and was significantly overexpressed in prostate cancer tissues (|log2FC| > 1, adjusted P < 0.05). Single-cell analysis across seven annotated cell types revealed specific FASN overexpression in epithelial cells, with expression progressively upregulated along pseudotime disease trajectories. Gene Set Variation Analysis (GSVA) demonstrated significant activation of oncogenic pathways — including PI3K-AKT-mTOR, androgen response, and early estrogen response — in FASN-high epithelial cells. Molecular docking confirmed favorable binding of NP and OP to FASN (binding affinities of −6.0 and −6.1 kcal/mol, respectively), and MD simulations showed that both complexes reached stable equilibrium with RMSD fluctuations below 0.3 nm. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations further yielded binding free energies of −19.70 kcal/mol (NP-FASN) and −17.24 kcal/mol (OP-FASN). Conclusion This study computationally identifies FASN as a potential molecular hub that may link phenolic EDC exposure to prostate cancer. Our bioinformatic analyses suggest a hypothetical mechanism involving pollutant-driven disruption of lipid metabolic reprogramming via FASN, potentially activating a pro-oncogenic network, which warrants future experimental validation.

Correction: Multi-modal emotional analysis in customer relation management and enhancing communication through integrated affective computing

Quantum logic operations and algorithms in a single 25-level atomic qudit

Marine upper-tropospheric rapid particle formation dominated by methanesulfonic acid

New particle formation (NPF) in the marine upper troposphere sustains one of the largest global aerosol reservoirs that seeds cloud condensation nuclei in the lower troposphere, with far-reaching implications for Earth’s radiative balance and climate. However, the underlying NPF mechanisms remain elusive, constituting a major uncertainty in climate projections. Here, we show that methanesulfonic acid (MSA), long considered only as a key boundary-layer precursor, dominates upper-tropospheric NPF across major oceans. Quantum-chemical and cluster dynamics simulations reveal that MSA enhances sulfuric acid (H 2 SO 4 )–ammonia (NH 3 ) nucleation rates by 1 to 3 orders of magnitude, far surpassing the well-established nitric acid (HNO 3 )–H 2 SO 4 –NH 3 mechanism, owing to stronger intracluster hydrogen bonds and low temperatures that stabilize clusters and render nucleation nearly barrierless. Further global three-dimensional modeling constrained by field measurements confirms that the proposed H 2 SO 4 –MSA–NH 3 nucleation pathway dominates the upper-tropospheric NPF over the Pacific, Atlantic, and Indian Oceans. Notably, this pathway contributes ~40% of global nucleation-induced Aitken- and accumulation-mode aerosols at 0.5 to 4 km altitudes, where most cloud water resides, and yields a net top-of-atmosphere radiation forcing of −1.75 W m −2 (~68% of the nucleation-induced response). This study offers a detailed mechanistic insight into marine upper-tropospheric NPF and improves representation of aerosol–cloud interactions, thereby reducing uncertainties in global climate projections.

Expression of Concern: Regulation of PKC Mediated Signaling by Calcium during Visceral Leishmaniasis

Fibroblast growth factor-23 as an early biomarker of ischemic acute kidney injury after partial nephrectomy: prospective observational study

Revisiting Zn-specific nucleation via a dimensionless factor to quantify interfacial electrochemistry of aqueous batteries

Abstract Zn-based aqueous batteries have attracted widespread research attention, while the lack of nucleation theory for electrochemical interactions at the Zn-water interface constrains efforts to suppress the thermodynamically spontaneous hydrogen evolution reaction and dendrite formation, thereby stalling practical development. Elucidating Zn electrodeposition in aqueous media requires Zn-specific nucleation theory and a descriptor to regulate interfacial electrochemistry. Conventional Li-based spherical nucleation models disregard Zn’s crystallography and the interfacial resistance that governs nucleation, thereby focusing on polarization variations. In this work, we reformulate the classical spherical nucleation theory derived by Li for the hexagonal close-packed structure of Zn and establish a dimensionless descriptor ( W f ) to quantitatively rationalize interfacial electrochemistry. W f synthesizes the polarization driving force and interfacial resistance into a stability metric. Higher W f values facilitate uniform Zn deposition, as evidenced by the literature. Accordingly, we develop a high- W f electrolyte to inhibit dendrites and side reactions, achieving over 700 h at 100% depth of discharge and 7660 cycles at 10 A g −1 in a Zn||NaV 3 O 8 cell. This work provides a fundamental nucleation theory and a generally applicable quantitative metric for the rational design of Zn-based aqueous batteries.

Correction for Astley et al., Global monitoring of the impact of the COVID-19 pandemic through online surveys sampled from the Facebook user base

Development of a Confined-Space Suitability Index (CSSI) using Least Absolute Shrinkage and Selection Operator (LASSO) regression: a pilot study for structured fitness-for-duty screening

Background Confined space work exposes workers to complex risks, including oxygen deficiency, hazardous gases, and physical strain, requiring structured criteria for fitness-for-duty screening. This study aimed to develop a Confined-Space Suitability Index (CSSI) based on routinely available health examination and functional test data. Methods A total of 111 workers were analyzed. Risk factors were classified into anthropometric and metabolic factors, functional and physiological factors, and lifestyle factors. Low cardiorespiratory fitness was defined using age- and sex-specific VO₂max reference thresholds from Korea Occupational Safety and Health Agency (KOSHA) H-43–2021 and Canadian Public Health Association reference values. Risk-factor weights were derived using LASSO regression, and internal validation was performed using leave-one-out cross-validation and bootstrap stability analysis. Results According to the revised CSSI criteria, 86 workers were classified as suitable, 19 as caution, and 6 as unsuitable. The independent specialist assessment classified 7 workers as unsuitable. In leave-one-out cross-validation, the CSSI showed an AUROC of 0.940 and an AUPRC of 0.567, with sensitivity of 0.833, specificity of 0.933, and negative predictive value of 0.990. In bootstrap stability analysis, dyslipidemia, low cardiorespiratory fitness, and hypertension were consistently selected. Conclusions The CSSI may serve as a structured screening and referral-support index for identifying workers who require additional specialist evaluation before confined space work. However, it should be interpreted as an auxiliary index rather than a replacement for specialist fitness-for-duty judgment.

Therapeutic Targeting of IL-17A-Driven PTGS2/NLRP3 Inflammasome Activation in Juvenile Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric myelodysplastic syndrome or myeloproliferative disorder for which hematopoietic stem cell transplantation remains the only curative option; however, outcomes are particularly poor in patients harboring PTPN11 (encodes SHP2 phosphatase) mutations. Using a Shp2E76K/+ JMML mouse model, we identify a pathogenic IL-17A/PTGS2/NLRP3 signaling axis that drives bone marrow inflammation, suppresses antitumor immunity, and promotes leukemic progression. Shp2E76K/+ mice exhibited profound immune dysregulation, characterized by expansion of regulatory T cells (Tregs), increased T-cell exhaustion, and impaired cytotoxic function with reduced CD4⁺ and CD8⁺ T-cell frequencies. Mechanistically, mutant macrophages upregulated IL-17A, triggering NLRP3 inflammasome activation, PTGS2 induction, caspase-1 cleavage, and IL-1β maturation, thereby amplifying inflammatory signaling within the marrow niche. Therapeutically, IL-17A neutralization suppressed inflammasome activity, while combined inhibition of NLRP3 and PTGS2 restored cytotoxic T-cell function, reduced systemic and marrow inflammation, reversed myeloproliferation, and significantly prolonged survival in Shp2E76K/+ mice. Importantly, ex vivo treatment of primary JMML patient samples with dual NLRP3/PTGS2 inhibition combined with MEK blockade significantly reduced leukemic progenitor colony formation, supporting translational relevance. In patient-derived xenograft models of PTPN11-mutant JMML, dual NLRP3/PTGS2 inhibition combined with MEK blockade most effectively reduced leukemic burden, decreased human CD45⁺ engraftment, and depleted leukemic CD34⁺CD38⁺ progenitors and GMPs while restoring MEP populations, resulting in significantly improved overall survival. Together, these findings establish IL-17A/PTGS2/NLRP3 signaling as a central driver of immune suppression and myeloid expansion in PTPN11-mutant JMML and highlight combinatorial anti-inflammatory targeting as a promising therapeutic strategy for this high-risk disease.

Rural residents’ cognition of healthy lifestyles: a qualitative study in Shanxi Province, China

Phytochrome B sets condensate number through graded nucleator states and seeding-site efficacy

Abstract Photobodies (PBs) are phytochrome B (phyB)-organized nuclear condensates that nucleate at defined subnuclear seeding sites and decrease in number with warming. How cells set PB number—and, more broadly, condensate number—remains poorly understood. Here we show that phyB’s output module (OPM) functions as a universal nucleator for all site-defined PB types, whereas the photosensory module (PSM) attenuates this activity, enabling environmental control. Consistently, missense substitutions in OPM genetically separate intrinsic nucleation potency from PSM-mediated regulation. Unexpectedly, the constitutively active phyB Y276H allele defines a hypoactive nucleation state, supporting graded active conformations with distinct nucleation potency. Temperature tunes PB number through two separable inputs—phyB thermal reversion (nucleator state) and temperature-responsive seeding-site efficacy—whose contributions vary across sites and cell types. Together, these results distinguish nucleation control (number) from growth control (size) and show that condensate number is jointly determined by nucleator state and seeding-site efficacy.

A centrin–Sfi1 myoneme fishnet powers ultrafast calcium-triggered contraction in the giant ciliate <i>Spirostomum ambiguum</i>

Spirostomum is a giant unicellular ciliate that contracts to a quarter of its body length in less than five milliseconds, achieving an order of magnitude higher fractional shortening rate than actomyosin-based systems. This ultrafast contraction is powered by myonemes, calcium-activated protein networks at the cortex whose biochemical mechanism remains unclear. We quantify changes in cortical microtubules, membrane ruffles, and the fishnet-like myoneme mesh during contraction, and develop multiscale models that connect local myoneme shortening to whole-cell shape change. Centrin and an Sfi1 homolog colocalize with the myoneme by immunofluorescence and localize to the myoneme by immunogold electron microscopy. Coarse-grained mesh simulations reproduce the measured deformations and show that fishnet geometry, together with volume conservation, leads to uniform contraction. Finally, we reconstitute a Spirostomum centrin–Sfi1 repeat complex in vitro and measure calcium-dependent compaction and self-association, supporting a molecular basis for myoneme contractility. Together, these results underpin a multiscale model in which calcium-responsive centrin–Sfi1 structures are the central contractile element in Spirostomum and suggest design principles for fast, calcium-triggered, chemomechanical contractile networks that operate without actomyosin or ATP.

Pharyngocutaneous fistula after total laryngectomy: Prevalence and risk factors

Objective To determine the prevalence and identify associated risk factors of pharyngocutaneous fistula following total laryngectomy. Methods Medical records of 160 patients diagnosed with laryngeal cancer between 2000–2021, subsequently undergoing total laryngectomy at Karolinska University Hospital, were analyzed for demographics, comorbidities, tumor characteristics, treatments and postoperative outcomes. Uni- and multivariate analyses were used to identify risk factors for pharyngocutaneous fistula. Results Pharyngocutaneous fistula developed in 28 patients (17.5%). Univariate analysis identified cardiovascular disease (OR 2.50; 95% CI 1.00–6.28), preoperative hemoglobin &lt;110 g/L (OR 5.34; 95% CI 1.74–16.45), prior radiotherapy (OR 3.78; 95% CI 1.24–11.52), preoperative tracheostomy (OR 2.44; 95% CI 1.05–5.72), pharyngectomy (OR 8.47; 95% CI 2.46–29.17), neck dissection (OR 2.52; 95% CI 1.06–6.00), pectoral flap reconstruction (OR 10.83; 95% CI 1.88–62.49) and postoperative infection (OR 28.44; 95% CI 9.00–89.81) as significant risk factors. In multivariate analysis only pharyngectomy (OR 7.18; 95% CI 1.08–47.63; p = 0.041) and postoperative infection (OR 24.94; 95% CI 6.66–93.46; p &lt; 0.001) remained independent. Conclusions Pharyngocutaneous fistula is a common complication occurring in 17.5% of patients following total laryngectomy. Pharyngectomy and postoperative infection are independent risk factors for fistula formation.

Type I interferon-activated NK cells control polycythemia vera in vivo

Polycythemia vera (PV) is a clonal hematopoietic stem cell (HSC) disorder resulting in overproduction of erythrocytes. While Interferon-a (IFN-a) has shown therapeutic efficacy in PV and other myeloproliferative neoplasms (MPN), its precise mechanism of action remains poorly understood. In this study, we identify natural killer (NK) cells as primary immune effectors responsive to IFN-a treatment in PV essential for disease control in vivo. Using a transgenic mouse model of PV, we demonstrate that IFN-a induces the expansion of CD27+ NK cells in the bone marrow. In patients with PV or ET undergoing IFN-a therapy, the frequency of CD56bright NK cells is increased and correlates with the molecular response. Depletion of NK cells abrogated the therapeutic effects of IFN-a. In vitro experiments demonstrate that NK cells preferentially killed Jak2VF mutant hematopoietic stem and progenitor cells (HSPCs) in a TNF-a dependent manner and independent of IFN-g or NKG2D. Notably, PV mice depleted of NK cells or lacking type-I interferon (IFN) receptor on NK cells showed accelerated disease progression in the absence of exogenous IFN-a. This suggests that direct sensing of basal levels of type-I IFNs by NK cells is essential for attenuating disease progression, emphasizing a critical role for NK cells in immune surveillance of MPN. These findings offer new insights into type-I IFN-mediated immune modulation in MPN and highlight the potential of NK cell activation to improve therapeutic outcomes.

Multimorbidity burden is associated with lower perceived health and life satisfaction in urban South Africa

Mapping interactions between disordered regions reveals promiscuity in biomolecular condensate formation

Path integration in complex number space

Desert ants and foraging rodents return home along surprisingly direct paths after meandering outward journeys. Traditional path integration models explain this through cumulative vector addition, yet struggle to account for the neurobiological mechanisms underlying this computation. Here we show that animal navigation emerges naturally when trajectories are represented in complex number space. We propose that head direction (HD) cells provide allocentric reference frame rotations, bilateral brainstem neurons (Chx10) control motion magnitudes within each frame, and left–right alternating theta sweeps in entorhinal–hippocampal maps continuously sample these bilateral activation states. Frame rotations at directional changes map to multiplication by unit complex numbers, converting egocentric motor commands into allocentric position tracking. This framework offers a neurobiologically grounded mathematics of navigation.

Exploring primary care health professionals’ perceived influence of their communication on HPV vaccine acceptance: Results from a national survey

Objective To evaluate primary care health professionals’ (PCHPs) perspectives on how their communication influences HPV vaccine acceptance, based on the self-perception theory. And to examine the factors associated with PCHPs’ perceived influence on HPV vaccine acceptance. Methods An online national survey was administered between May and July 2022 to PCHPs involved in HPV vaccination for children ages 9–12 years old. Survey items comprised of PCHPs’ demographics, clinic settings, and selected HPV communication measures, such as influence of vaccine communication, strategies and challenges, and past HPV vaccine communication training. Logistic regression models assessed factors associated with PCHPs’ perceived influence of their communication on HPV vaccine acceptance. Results The majority of PCHPs felt their communication greatly influenced HPV vaccine acceptance. Compared to PCHPs who thought that communication had little or some influence on HPV vaccine acceptance, PCHPs who thought their communication greatly influenced HPV vaccine acceptance were more likely to: 1) use presumptive recommendations (aOR: 1.32; 95% CI: 1.11, 1.57), 2) report parental concerns about HPV vaccination promoting sexual activity (aOR:1.26, 95% CI: 1.06, 1.51), and 3) have had HPV vaccine communication training on how to address parental HPV vaccine hesitancy (aOR:1.25; 95% CI: 1.02, 1.54). Conclusion This study demonstrates the pivotal role of vaccine communication in influencing HPV vaccine acceptance among PCHPs. Tailored vaccine communication training that involves the entire primary care team and equips them with effective communication techniques is essential to increase PCHP’s confidence in vaccine conversations and competence in making HPV vaccine recommendations. HPV vaccine communication should also include content that promotes the cancer preventive role of HPV vaccine and debunks the myth around HPV vaccination promoting sexual activity.

Long-term stability of posttranscriptional genetic silencing of BCL11A using a shmiR vector in Sickle Cell Disease

Sickle cell disease (SCD) is characterized by chronic hemolysis, painful vaso-occlusive episodes (VOE) and end organ damage. High levels of fetal hemoglobin (HbF) attenuate the disease phenotype. We used a lentivirus vector (LVV) expressing an shRNA embedded in a microRNA (shmiR) targeting BCL11A in erythrocytes to induce HbF in a first-in-human pilot study in SCD. The purpose of the study was to assess hematopoietic stem/progenitor cells (HSPCs) collection, transduction parameters, safety, HbF induction and durability. Eleven eligible patients with SCD had HSC collection. Plerixafor-mobilized peripheral blood HSCs required for manufacturing were obtained in one mobilization cycle for 10/11 subjects and 11/11 patient products were successfully manufactured with a median time to release of product of 39 days. Ten patients were infused with autologous HSCs transduced with the shmiR vector. Engraftment occurred in all 10 patients. With a median follow-up of 58 months (range: 35-82) after infusion, no adverse events attributed to the gene vector have occurred. Transduction efficiency was 93.1%. One patient demonstrated low engraftment of transduced cells and had suboptimal HbF induction. In the remaining 9 patients, at 2 years post-treatment peripheral blood demonstrated 71% F cells with 11.9 pg HbF/F cells, both stable in 9 patients with ≥48 months follow-up. All patients who had VOEs prior to gene therapy demonstrated sustained mitigation of pain events. These data demonstrate excellent manufacturing efficiency and safety, with efficacy of targeting BCL11A using a shmiR LVV, and long-term durability of the shmiR vector, leading to a pivotal multi-site phase 2 trial currently underway (NCT05353647).