Browse Articles

Public data openness and health expenditure: evidence from macro–micro analyses in China

Dual-modality microwave–optical platform for label-free electrodynamic differentiation of cortisol and DHEA biomarkers

Altering host microenvironment is critical for success of cell therapy for osteogenesis imperfecta

A low-light image enhancement model integrating structural and texture perception

Evaluation of efficacy and safety of use of Codubix and Codubix S cranial implants

Dimensional psychopathology explains functional disability better than ICD-10 categories

TIMAP depletion impairs BMP signaling by accelerating SMURF1-mediated SMAD degradation in neuroblastoma cells

Abstract The protein phosphatase 1 (PP1) regulatory subunit, TGF-β inhibited membrane-associated protein (TIMAP), is highly expressed in neuronal cells, yet its role in regulating PP1 activity remains poorly understood. To investigate this, TIMAP was stably depleted in SH-SY5Y human neuroblastoma cells. Transcriptomic analysis identified 614 differentially expressed genes upon TIMAP depletion, with gene ontology analysis highlighting significant disruption of the bone morphogenetic protein (BMP) signaling pathway. Functional studies showed that TIMAP depletion reduced SMAD1 protein levels following stimulation with BMP7. While the activation-dependent C-terminal phosphorylation of SMAD1/5/8 remained unaffected, its nuclear translocation was strongly impaired. This defect is caused by the accelerated proteasomal degradation of the cytoplasmic SMAD1 pool, which limits the amount of protein available for nuclear import. Our data demonstrate that TIMAP directs PP1 to the SMAD1 linker region to control phosphorylation dynamics. In the absence of TIMAP, elevated Ser206 phosphorylation in the SMAD1 linker region recruits the ubiquitin ligase SMURF1, leading to increased SMAD1 ubiquitination and clearance. These findings reveal that TIMAP maintains the integrity of BMP signaling by targeting PP1 to dephosphorylate regulatory sites, thereby preventing ubiquitin-mediated degradation and promoting effective nuclear functions.

Unsupported respiratory effort is associated with myocardial injury and pulmonary occlusive microvascular changes in experimental acute lung injury

Abstract Strenuous respiratory effort has been proposed as a second hit for the lungs, labeled as “patient self-inflicted lung injury” (P-SILI). This secondary exploratory analysis evaluated whether insufficient respiratory support is associated with biventricular myocardial injury and pulmonary microvascular ultrastructural changes in experimental acute lung injury. In rats, lung injury was induced through surfactant depletion, followed by 3 h of unsupported (standard oxygen therapy, 2L/min) or supported ventilation: protective mechanical ventilation (MV), continuous positive airway pressure (CPAP) 6 cmH 2 O, or high-flow nasal oxygen (HFNO) 4L/min. Subjects were assessed through general monitoring, arterial blood gas analysis, esophageal manometry (inspiratory effort), surface electromyography on the abdominal wall (expiratory effort), echocardiography (right ventricular outflow), and coagulation dysfunction analysis. An exploratory histological hypothesis-generating study on the right and left ventricular (RV and LV) myocardium was performed in all animals, and a quantitative scanning electron microscopy-based analysis of luminal permeability in small pulmonary vessels was completed only in four subjects per injured group. The primary endpoint was RV myocardial injury, while LV injury and pulmonary microvascular changes were considered secondary endpoints. The unsupported group presented higher heart rate, hypercapnia, increased arterial lactate levels, respiratory variation in pulmonary peak flow velocity, RV and LV myocardial injury, and incipient alterations in coagulation compared to MV and CPAP (all p  < 0.05). All support therapies were associated with lower myocardial injury score: MV and CPAP showed the lowest RV injury, and HFNO the highest. Only MV was strongly associated with lower LV injury score (all p  < 0.05). The Standard oxygen therapy and HFNO groups showed significantly higher luminal occlusion in small pulmonary vessels, consisting of erythrocyte-rich intravascular aggregates and amorphous material adherent to the vascular wall (all p  < 0.05). Unsupported respiratory effort was associated with biventricular myocardial injury and pulmonary microvascular ultrastructural findings characterized by occlusive intravascular aggregates compatible with early microthrombotic changes. These findings support the concept that underassistance injury may extend beyond the lung parenchyma and respiratory muscles to involve cardiovascular and pulmonary microvascular domains.

Leveraging big data and green strategies to enhance manufacturing sustainability in developing economies

Reddit deplatforming and cohort mixing in generalist Voat communities

Copula based fusion of clinical and gene expression machine learning risk scores for breast cancer risk stratification

Abstract Clinical and gene-expression models are both used to predict breast cancer outcomes, but they are often combined using simple linear rules that do not account for how their risk scores relate. Using the METABRIC breast cancer cohort, we examined whether directly modeling the joint relationship between clinical and gene-expression machine-learning risk scores could improve risk stratification for 5-year cancer-specific mortality. We created a binary 5-year cancer-death outcome and defined two predictor views: a clinical view based on demographic, tumor, and treatment-related variables, and a gene-expression view based on mRNA expression features. We trained several supervised classifiers and used 5-fold cross-validated predicted probabilities as out-of-fold risk scores. These scores were converted to pseudo-observations on $$(0,1)^2$$ and used to fit Gaussian, Clayton, Gumbel, and Frank copulas. In the primary METABRIC analysis, the clinical model showed stronger discrimination (AUC 0.783) than the gene-expression model (AUC 0.721). Among the copula families considered, the Frank copula yielded the smallest goodness-of-fit statistic, while the Gaussian copula showed nearly identical performance. Although the copula-fused score did not improve ROC-AUC relative to the clinical model, joint risk stratification based on the clinical and gene-expression scores identified clear differences in long-term survival, with patients in the high-both group experiencing the least favorable outcomes. Competing-risks analysis showed the same overall pattern for the cumulative incidence of cancer death. In an independent TCGA cohort, we conducted an external evaluation under a reduced harmonized specification using shared predictors and a common 5-year overall-mortality endpoint. The copula-fused score had discrimination comparable to the individual and simple-fusion scores, with substantially overlapping confidence intervals. All three scores underwent the same METABRIC-based recalibration procedure before calibration was evaluated using the Brier score, calibration slope, calibration intercept, integrated calibration index, Hosmer-Lemeshow diagnostic, and reliability curves. No gene met the prespecified stability criterion under repeated cross-validated permutation importance; gene-level findings were therefore treated as exploratory biological context rather than evidence of stable predictive drivers. We frame this work as a methodological and exploratory study of interpretable, dependence-aware score fusion: The results show that copula modeling provides an explicit description of dependence between clinical and gene-expression risk scores and supports descriptive joint score-group analyses. The study does not establish superior prediction, validated clinical risk categories, or clinical utility.

Leaf photosynthetic characteristics and fruit quality of Actinidia arguta as affected by slope aspect and gradient

Diagnostic performance and clinical utility of targeted next-generation sequencing for diagnosing lower respiratory tract infections in intensive care unit patients

Chemical characterization and cardiovascular effects of an oxime derived from a metabolite of Senecio nutans

Abstract Senecio nutans Sch. Bip. (Asteraceae) is traditionally used in Andean medicine to alleviate symptoms associated with high-altitude exposure, such as headaches, fatigue, and nausea. Previous studies have identified the p -hydroxyacetophenone derivative 4-hydroxy-3-(isopenten-2-yl) acetophenone ( Sn-IV ) as a bioactive metabolite with vasodilatory properties. This study aimed to evaluate whether oxime derivatization of Sn-IV enhances its cardiovascular activity and to compare the pharmacological effects of the synthetic oxime derivative OxSn-IV with those of the parent metabolite. OxSn-IV and structurally related oxime derivatives were synthesized from acetophenone precursors. The vascular effects of Sn-IV and OxSn-IV were evaluated in normotensive rats by measuring arterial blood pressure in vivo. Cardiac effects were evaluated in intact hearts (Langendorff), atrial preparations (organ bath), and in isolated ventricular myocytes (photometry). OxSn-IV significantly reduced mean arterial pressure in normotensive rats, whereas the parent metabolite Sn-IV showed minimal effects. OxSn-IV also attenuated the pressor response induced by phenylephrine and reduced heart rate. In isolated hearts, the compound decreased left ventricular pressure, dP/dtmax, and coronary perfusion pressure, showing negative inotropic effects. In isolated atria, OxSn-IV produced a concentration-dependent reduction in beating rate. OxSn-IV produced a negative inotropic effect on systolic calcium levels, thus sarcomere shortening. Oxime derivatization of the natural metabolite Sn-IV markedly enhances its cardiovascular activity. The results provide experimental evidence supporting the traditional use of S. nutans and suggest that oxime derivatives of its metabolites may represent promising scaffolds for the development of new cardiovascular agents.

Hedgehog/GLI1 regulates EMT and cancer stem cell properties via the GLI1-Bmi1 axis in diffuse large B-cell lymphoma

Trans-stenotic pressure drop estimation from PC-MRI and ultrasound imaging velocimetry using a modified Bernoulli equation

Abstract Accurate non-invasive estimation of trans-stenotic pressure drops remains a challenge. In clinical practice, pressure drops are often estimated from velocity measurements using Bernoulli-based formulas, but these simplified relations do not explicitly account for how pressure losses change with the flow regime. Here, we introduce a modified Bernoulli (MB) formulation that incorporates regime-dependent pressure losses through a Reynolds-number-dependent loss coefficient. Steady in-vitro experiments were performed in an idealized stenosis model over physiologically relevant flow rates (0.65–3.9 L/min), combining direct pressure measurements with ultrasound imaging velocimetry (UIV) and phase-contrast magnetic resonance imaging (PC-MRI) to measure velocities. The MB model was calibrated from the measured pressure drops and then evaluated against the simplified Bernoulli (SB) and extended Bernoulli (EB) formulations. Over the tested flow regime, MB agreed best with the measurements (typically within about ±10% ). SB and EB showed larger biases, with errors of roughly 10–55% (SB) and -15 to 25%−(EB), and overestimated the pressure drop in the clinically relevant range. We additionally quantified the effect of PC-MRI in-plane pixel size on MRI-based pressure estimates. Coarse in-plane pixel size of 1.33 mm, corresponding to only approximately 3–4 pixels across the 3.3 mm throat radius of the 6.6 mm stenosis throat, led to systematic underestimation of flow rate and bulk velocity (about − 34 to − 44%) and, consequently, of the MB-predicted pressure drop (about − 52 to − 62%). In contrast, the peak throat velocity was substantially less sensitive to pixel size, resulting in smaller estimation errors (about − 13 to − 18.7%) when used as input for the MB. Overall, the results demonstrate that accounting for flow-regime-dependent loss mechanisms enhances pressure drop estimation, and that sufficient sampling of the stenotic throat is crucial for MRI-based flow rate and pressure drop estimation. In addition, peak-velocity-based MB pressure drop estimations are less sensitive to pixel size.

RAS inhibition limits oncogenic signaling and tumorigenesis in neuroblastoma regardless of RAS mutational status

Abstract Neuroblastoma (NBL) is a rare and aggressive pediatric malignancy with a 5-year survival rate of 40–50% for patients diagnosed with high-risk disease. NBLs arise in the sympathetic nervous system and causes 11% of all pediatric cancer deaths. MYCN amplification or overexpression drives 22% of NBL cases while deregulation of genes including c-MYC, ALK, PHOX2B, and LIN28B also plays a critical role in NBL initiation and progression. Although RAS proto-oncogenes are rarely mutated in primary NBL (< 2%), studies suggest that elevated RAS activity may contribute to NBL tumorigenesis and progression. Here, we explore targeted RAS inhibition as a potential therapeutic strategy for NBL. Using mutation-specific inhibitors of KRAS, we demonstrate the importance of mutant KRAS in NBL. Furthermore, using anti-RAS biologics and a pan RAS inhibitor, we also demonstrate the importance of wild type (WT) RAS activity in non-RAS mutant NBLs. Direct RAS inhibition decreases NBL cell proliferation, colony formation, and migration in vitro in NBL lines differing in MYCN and RAS mutation status. Furthermore, inhibition of WT RAS suppresses the growth of specific NBL lines in vivo. Our findings suggest that targeted RAS inhibition, even in the absence of RAS mutation, may represent a promising therapeutic approach for NBL patients.

Primary hepatopancreatobiliary lymphoma: epidemiology, clinical features, and treatment outcomes

Loneliness and social isolation as predictors of pain medication use transitions in older adults

Abstract Older adults are at increased risk of loneliness, social isolation and use of analgesics such as over-the-counter (OTC) medications and opioids. While evidence suggest that loneliness and social isolation may influence patterns of pain medication use, longitudinal studies remain limited. Data from the Health and Retirement Study (2014–2022) were analysed for 9,454 US adults aged 50+. Continuous-time multistate Markov models examined how social isolation and loneliness were associated with the likelihood of transitioning between states of medication use, non-use, and death whilst controlling for sociodemographic and health-related factors. Loneliness was associated with higher risks of initiating both opioids (HR = 1.19, 95%CI: 1.03–1.37) and OTC (HR = 1.12, 95%CI: 1.01–1.25). Conversely, social isolation was not associated with transitions into opioid use, but it was associated with a reduced likelihood of initiating OTC medication (HR = 0.85, 95%CI: 0.77–0.95). Neither factor was associated with medication discontinuation. Loneliness and social isolation are thus differentially related to pain medication transitions in older adults; whereas loneliness may contribute to increased likelihood of initiating medication use, social isolation relates to lower OTC uptake. These findings highlight the need to consider subjective and objective social connection as critical components of safer pain management in older adults.

Relationship between knowledge, adherence-related behaviors and self-management with response to monoclonal antibody therapy in patients with severe asthma

Abstract This study explores the relationship between patient activation, adherence behaviors, asthma knowledge, and response to monoclonal antibody (mAb) therapy in severe eosinophilic asthma (SEA). Despite advances in mAb therapies, some SEA patients continue to experience uncontrolled symptoms. Understanding these factors could lead to more effective, personalized treatment strategies. Participants diagnosed with SEA and undergoing mAb therapy for 6-9 months were recruited from three German university outpatient clinics. They were categorized using the Biologics Asthma Response Score (BARS) into responders, partial responders, and non-responders. Data collection focused on demographic details, lung function, medication history, patient activation (PAM13-D), and adherence (A14 questionnaire). Statistical analyses assessed the impact of adherence and knowledge on treatment outcomes. Of the 140 participants, 61% were responders, 24% partial responders, and 15% non-responders. Age, sex distribution, smoking status, pack-years, eosinophil levels, ExNO and lung function parameters were comparable across response groups. A14 scores and asthma knowledge differed significantly across response groups, whereas PAM13-D did not. In ordinal logistic regression, asthma knowledge remained associated with BARS-defined response category after adjustment. A negative attitude towards drugs was associated with response category in univariate analysis, but this association was attenuated after adjustment. Better asthma knowledge was associated with BARS-defined response to mAb therapy, while PAM13-D and overall A14 score were not independently associated with response. Medication attitude may still be clinically relevant, but their association with response should be interpreted cautiously. These findings support a patient-centered approach that considers asthma knowledge, adherence-related behaviors and medication attitudes during biologic treatment. Prospective studies are needed to determine whether targeted education and adherence support can improve clinical outcomes.