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BACKGROUND: Whether primary or just as a complication from the progression of pulmonary arterial hypertension (PAH), thrombosis seems to be an important player in this condition. The cross-talk between red blood cells (RBCs) and pulmonary microvascular endothelial cells (PMVECs) and their role in PAH remain undefined. OBJECTIVES: The goals of this study were to assess the role of RBC-PMVEC interaction in microvascular thrombosis and thrombotic vascular remodeling under hypoxic conditions. METHODS: We established an in vitro hypoxic co-incubation model of RBC and PMVEC as well as a hypoxic mice model. We investigated erythrophagocytosis (EP), ferroptosis, thrombosis tendency, and pulmonary hemodynamics in experimental PAH. RESULTS: We showed that increased EP in PMVEC triggered ferroptosis, enhanced procoagulant activity, and exacerbated vessel remodeling under hypoxic conditions. In the PAH mice model induced by chronic hypoxia, EP-induced ferroptosis followed by upregulated TMEM16F led to a high tendency of thrombus formation and thrombotic vascular remodeling. Inhibition of ferroptosis or silence of TMEM16F could alleviate hypercoagulable phenotype, reverse right ventricular (RV) systolic pressure, RV hypertrophy index, and remodeling of pulmonary vessels. CONCLUSIONS: These results illustrate the pathogenic RBC-PMVEC interactions in PAH. Inhibition EP, ferroptosis, or TMEM16F could be a novel therapeutic target to prevent PAH development and thrombotic complications.

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Insect herbivores adapt and develop strategies to counteract plant chemical defenses. The aphid Uroleucon formosanum is a serious sap-sucking pest that infests lettuces containing toxic sesquiterpene lactones (STLs). Herein, we employed a combination of genome sequencing and RNA-seq transcriptome profiling to understand the mechanisms underlying phytotoxin tolerance in U. formosanum. We generated the first chromosome-level genome assembly for U. formosanum, with a total size of 453.26 Mb and a scaffold N50 of 33.22 Mb. Comparative genomic analyses revealed an enrichment of signals for positive selection and gene family expansion in immune-related pathways. Specifically, the expanded set of heat shock protein 70 (HSP70) genes showed upregulation after treatment with lactucin, suggesting that they may play a role in the immune response against STLs. The expression of takeout-like genes and cuticle-associated genes was also significantly increased in the lactucin-treated samples. Additionally, 53 cytochrome P450 monooxygenase, 30 carboxylesterase, 19 glutathione S-transferase, 32 uridine diphosphate glycosyltransferase and 63 ATP-binding cassette (ABC) transporter genes were identified in the U. formosanum genome. CYP4C1, CYP6A13 and 7 ABC genes were strongly upregulated in response to lactucin treatment, indicating the involvement of detoxifying enzymes in the tolerance of U. formosanum to STLs. Our findings suggest that the cuticle barrier, immune response and enzyme-mediated metabolic detoxification jointly enhance the tolerance of U. formosanum to phytotoxins and promote its adaptation to host plants. This study presents a valuable genomic resource and provides insights into insect adaptation to plant chemical challenges and future technological developments for pest management.

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Light-dependent reduction of carbon dioxide (CO2) into value-added products can be catalyzed by a variety of molecular complexes. Here we report a rare example of a structurally characterized artificial enzyme, resulting from the combination of a heme binding protein, heme oxygenase, with cobalt-protoporphyrin IX, with good activity for the photoreduction of CO2 to carbon monoxide (CO). Using a copper-based photosensitizer, thus making the photosystem free of noble metals, a large turnover frequency value of ∼616 h-1, a turnover value of ∼589, after 3 h reaction, and a CO vs H2 selectivity of 72% were obtained, establishing a record among previously reported artificial CO2 reductases. Thorough photophysical studies allowed tracking of reaction intermediates and provided insights into the reaction mechanism. Thanks to a high-resolution crystal structure of the artificial enzyme, both in the absence and in the presence of the protein-bound CO2 substrate, a rational site-directed mutagenesis approach was used to study the effect of some modifications of the active site on the activity.

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OBJECTIVE: To assess the impact of a diagnostic test stewardship intervention focused on tracheal aspirate cultures. DESIGN: Quality improvement intervention. SETTING: Tertiary care pediatric intensive care unit (PICU). PATIENTS: Mechanically ventilated children admitted between 9/2018 and 8/2022. METHODS: We developed and implemented a consensus guideline for obtaining tracheal aspirate cultures through a series of Plan-Do-Study-Act cycles. Change in culture rates and broad-spectrum antibiotic days of therapy (DOT) per 100 ventilator days were analyzed using statistical process control charts. A secondary analysis comparing the preintervention baseline (9/2018-8/2020) to the postintervention period (9/2020-8/2021) was performed using Poisson regression. RESULTS: The monthly tracheal aspirate culture rate prior to the COVID-19 pandemic (9/2018-3/2020) was 4.6 per 100 ventilator days. A centerline shift to 3.1 cultures per 100 ventilator days occurred in 4/2020, followed by a second shift to 2.0 cultures per 100 ventilator days in 12/2020 after guideline implementation. In our secondary analysis, the monthly tracheal aspirate culture rate decreased from 4.3 cultures preintervention (9/2018-8/2020) to 2.3 cultures per 100 ventilator days postintervention (9/2020-8/2021) (IRR 0.52, 95% CI 0.47-0.59, P < 0.01). Decreases in tracheal aspirate culture use were driven by decreases in inappropriate cultures. Treatment of ventilator-associated infections decreased from 1.0 to 0.7 antibiotic courses per 100 ventilator days (P = 0.03). There was no increase in mortality, length of stay, readmissions, or ventilator-associated pneumonia postintervention. CONCLUSION: A diagnostic test stewardship intervention was both safe and effective in reducing the rate of tracheal aspirate cultures and treatment of ventilator-associated infections in a tertiary PICU.

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BACKGROUND: Cefoperazone/sulbactam is commonly prescribed for the treatment of infected patients with cirrhosis. AIM: To investigate the effect of cefoperazone/sulbactam on coagulation in cirrhotic patients and assess the effectiveness of vitamin K1 supplementation in preventing cefoperazone/sulbactam-induced coagulation disorders. METHOD: This retrospective cohort study compared coagulation function in 217 cirrhotic patients who received cefoperazone/sulbactam with and without vitamin K1 supplementation (vitamin K1 group, n = 108; non-vitamin K1 group, n = 109). Propensity score matching (PSM) was used to to reduce confounders' influence, the SHapley additive exPlanations (SHAP) model to explore the importance of each variable in coagulation disorders. RESULTS: In the non-vitamin K1 group, the post-treatment prothrombin time (PT) was 16.5 ± 6.5 s and the activated partial thromboplastin time (aPTT) was 34.8 ± 9.4 s. These were significantly higher than pre-treatment values (PT: 14.6 ± 2.4 s, p = 0.005; aPTT: 30.4 ± 5.9 s, p < 0.001). In the vitamin K1 group, no differences were observed in PT, thrombin time, or platelet count, except for a slightly elevated post-treatment aPTT (37.0 ± 10.4 s) compared to that of pre-treatment (34.4 ± 7.2 s, p = 0.033). The vitamin K1 group exhibited a lower risk of PT prolongation (OR: 0.211, 95% CI: 0.047-0.678) and coagulation disorders (OR: 0.257, 95% CI: 0.126-0.499) compared to that of the non-vitamin K1 group. Propensity score matching analysis confirmed a reduced risk in the vitamin K1 group for prolonged PT (OR: 0.128, 95% CI: 0.007-0.754) and coagulation disorders (OR: 0.222, 95% CI: 0.076-0.575). Additionally, the vitamin K1 group exhibited lower incidences of PT prolongation, aPTT prolongation, bleeding, and coagulation dysfunction compared to the non-vitamin K1 group. CONCLUSION: Cefoperazone/sulbactam use may be linked to a higher risk of PT prolongation and coagulation disorders in cirrhotic patients. Prophylactic use of vitamin K1 can effectively reduce the risk.

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BACKGROUND: A predominate azole-resistant Candida tropicalis clade 4 genotype causing candidemia has been detected in not only Taiwan but also China, Singapore, and Australia. It can also be detected on fruit surfaces. In addition to determining distribution and drug susceptibilities of pathogenic yeasts in environments of intensive care units of 25 hospitals in Taiwan, we would also like to investigate whether the azole-resistant C. tropicalis exists in Taiwan's hospital environment. METHODS: The swabs of hospital environments were collected from August to November in 2020 and were cultured for yeasts. The yeasts were identified by rDNA sequence and the antifungal susceptibilities of those isolates were determined by the broth microdilution method. RESULTS: The average yeast-culture rate of hospitals was 9.4% (217/2299). Sinks had the highest yeast-positive culture rate (32.7%), followed by bedside tables (28.9%), floors (26.0%), water-dispenser buttons (23.8%), and TV controller/touch panels (19.0%). Of 262 identified isolates, Candida parapsilosis was the most common species, accounting for 22.1%, followed by Filobasidium uniguttulatum (18.3%), Candida albicans (9.5%), C. tropicalis (8.0%), Candida glabrata (Nakaseomyces glabratus) (6.9%), and 30 other species (35.1%). Of the 21 C. tropicalis isolates from 11 units in 9 hospitals, 15 diploid sequence types (DSTs) were identified. The two DST506 fluconazole-resistant ones belonged to clade 4. CONCLUSION: We detected not only various pathogenic yeast species but also the predominant clade 4 genotype of azole-resistant C. tropicalis. Our findings highlight and re-emphasize the importance of regular cleaning and disinfection practices.

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Aims: A strategy based on therapeutic drug monitoring and population pharmacokinetic (popPK) models would likely increase the rate of clinical remission (CR) after infliximab (IFX) induction in patients with Crohn's disease (CD). This study aimed to evaluate the relationship between early IFX levels and antibodies to infliximab (ATI) and CR at week 14 and simulate the probability of attaining the identified exposure target. Methods: Patients with CD (n = 140) treated with IFX were enrolled to develop the popPK model. Of these, 43 moderate-to-severe patients with CD were followed up at week 14. Simulations were performed on patients with different dosage regimens and covariates. Results: IFX levels >20.08 µg/mL at week 2, >18.44 µg/mL at week 6, and >3.08 µg/mL at week 14 were linked to CR. A one-compartment model fit the data best. The covariates influencing clearance were fat free mass, albumin and ATI levels. To achieve IFX levels >20.08 µg/mL at week 2, ≥400 mg IFX was predicted to be required in over 50% patients with 45-70 kg and 35-45 g/L albumin, except for patients with 70 kg and 30 g/L albumin. Conclusion: IFX levels >20.08 µg/mL at week 2 and absence of ATI at week 14 are associated with CR. Optimising IFX induction dosing will be critical to achieve the target of early IFX levels associated with CR.

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Fresh yak meat is highly nutritious and prone to spoilage, so developing suitable preservation methods is crucial. In this study, hydrogel coatings composed of konjac glucomannan, Lactiplantibacillus plantarum and gallic acid (KGX) were applied to preserve fresh yak meat under ice temperature (-1 °C). After 16 days, KGX group showed lowest total viable count (5.3 ± 0.1 log cfu/g) and total volatile basic nitrogen (13.02 ± 1.40 mg/100 g), which did not exceed the relevant standards of fresh meat. Combined assessments of color, texture, pH, drip loss rate, and thiobarbituric acid reactive substances indicated that KGX coating effectively prolonged yak meat preservation. High-throughput sequencing revealed that KGX coating effectively reduced the abundance of Pseudomonas and Candida. The application of L. plantarum hydrogel coatings in conjunction with ice temperature increased the shelf life of fresh yak meat to 16-20 days, suggesting its potential as a viable preservation method for fresh meat.

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Liquid crystalline (LC) materials are especially suited for the preparation of active three-dimensional (3D) and 4D microstructures using two-photon laser printing. To achieve the desired actuation, the alignment of the LCs has to be controlled during the printing process. In most cases studied before, the alignment relied on surface modifications and complex alignment patterns and concomitant actuation were not possible. Here, we introduce a strategy for spatially aligning LC domains in three-dimensional space by using 3D-printed polydimethylsiloxane-based microscaffolds as confinement barriers, which induce the desired director field. The director field resulting from the boundary conditions is calculated with Landau de Gennes theory and validated by comparing experimentally measured and theoretically predicted birefringence patterns. We demonstrate our procedures for structures of varying complexity and then employed them to fabricate 4D microstructures that show the desired actuation. Overall, we obtain excellent agreement between theory and experiment. This opens the door for rational design of functional materials for 4D (micro)printing in the future.

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BACKGROUND: Hearing loss and lifestyle factors have been associated with cognitive impairment. We aimed to explore the joint association of combined healthy lifestyle factors and hearing loss with cognitive impairment, which has been scarcely studied. METHODS: This baseline study used data from the CHOICE-Cohort study (Chinese Hearing Solution for Improvement of Cognition in Elders). Hearing loss was assessed by the better-ear pure-tone average (BPTA). A composite healthy lifestyle score was built based on never smoking, never drinking, regular physical activity, and balanced diet. Cognitive impairment was diagnosed by the Mini-Mental State Examination (MMSE) score of less than 24. RESULTS: We included 17057 participants aged 60 years or older in China (mean age 69.8 [SD 6.2] years, 55.7% female). Among the participants, 48.3% (n=8234) had mild hearing loss, and 25.8% (n=4395) had moderate or greater hearing loss. The proportion of participants with healthy lifestyle scores of 0-1, 2, 3, and 4 was 14.9% (n=2539), 29.3% (n=5000), 37.4% (n=6386), and 18.4% (n=3132), respectively. 29.6% (n=5057) participants had cognitive impairment. When compared to those with normal hearing and healthy lifestyle (scores of 3-4), participants with hearing loss plus unhealthy lifestyle (scores of 0-2) exhibited approximately twofold increased risk of cognitive impairment (OR=1.92, 95% CI 1.70-2.18). Conversely, the risk was greatly attenuated by adherence to healthy lifestyle in individuals with hearing loss (OR=1.57, 95% CI 1.40-1.76). CONCLUSIONS: Our findings demonstrated adherence to a broad range of healthy lifestyle factors was associated with a significantly lower risk of cognitive impairment among participants with hearing loss.

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Copper smelter dust, a typical hazardous waste that is abundant in valuable heavy metals, holds the potential to be regarded as a promising resource. This study introduces a new approach that integrates chlorination roasting and cascade condensation to efficiently recover heavy metals from copper smelter dust. The findings demonstrate the successful separation of heavy metals (Cu, Pb, and Zn) as chlorides at nearly 100% efficiency while also effectively converting trivalent arsenic (As(III)) into pentavalent arsenic (As(V)) and immobilizing it in the roasting residues, thereby reducing environmental risk. Through the utilization of thermogravimetric mass spectrum analysis and thermodynamic equilibrium calculations, the chlorination process for heavy metals was investigated, revealing both direct and indirect chlorination processes. Additionally, the study resulted in the development of a CuO-based multiple-metals electrocatalyst from the oxidized roasting-recovered heavy metal chlorides, exhibiting significantly enhanced catalytic activity and faradaic efficiency for the electroreduction of CO2 into CO and CH4 compared to pure CuO electrocatalyst under similar electrocatalytic conditions. Overall, this work presents a sustainable and scalable method and new insights for addressing environmental risks while repurposing copper smelter dust.

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In the context of oligometastatic renal cell carcinoma (RCC), local treatment with stereotactic body radiotherapy (SBRT) may improve oncologic outcomes. However, the location and size can often pose a technical challenge in standard SBRT delivery, and the dose is potentially limited by nearby organs at risk (OARs). Online adaptive radiotherapy (oART) improves radiation delivery by personalizing high-dose fractions to account for daily stochastic variations in patient anatomy or setup. The oART process aims to maximize tumor control and enhances precision by tailoring to a more accurate representation of a patient in near-real time. The proceeding re-optimization can mitigate the uncertainty inherent in the traditional radiation delivery workflow and precludes the need for larger margins that account for anatomical variations and setup errors. Here, we describe a case of oligometastatic RCC with a bulky (>300 cm3) pleural-based left lower lobe mass extending into the upper abdomen treated via personalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR). Three fractions were delivered four weeks apart allowing for tumor shrinkage of these bulky lesions, and oART permitted on-table adaptation of the plan without traditional re-simulation and re-planning required during off-line adaptive radiotherapy. The plan was designed for the Ethos linear accelerator (Varian Medical Systems, Inc., Palo Alto, CA, USA). The prescription dose was 36 Gray (Gy) in three fractions, and the adapted plan was selected in each treatment over the scheduled plan due to better target coverage and reversal of OAR dose violations. The adapted plan met all OAR dose constraints, and it achieved higher target coverage in the first two PULSAR fractions compared to the scheduled plan. In the third fraction, the cumulative point dose was approaching the maximum heart tolerance, and target coverage was accordingly compromised based on clinical judgment. There was evidence of tumor regression throughout the course of treatment, and the patient did not develop any significant radiation-related toxicities. Follow-up imaging has demonstrated the overall stable size of her lesion without any evidence of disease progression. Our case reflects the benefit of adaptive SBRT delivery to a bulky mass near multiple OARs in the setting of oligometastatic RCC. The adapted plan allowed for prioritization of critical structures on a fraction-by-fraction basis while preserving the therapeutic intent of SBRT. Further integration of advanced imaging techniques, optimal disease-specific systemic immunotherapies or targeted therapies, and refinement of patient selection will be crucial in identifying which patients would most benefit from an adaptive approach.

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Introduction: This study investigates how parental styles, basic empathy, and family violence influence adolescents' bystander behaviors in school bullying. Methods: A survey was conducted with 1,067 students from three middle schools in southern China. Multifactor logistic regression and a moderated mediation model were employed to analyze the relationships between positive and negative parental styles, basic empathy, and bystander behaviors. Results: The study found significant correlations and predictive relationships: Positive parental styles were strongly associated with increased basic empathy (r = 0.29, p < 0.01) and behaviors that protect victims (r = 0.29, p < 0.01). In contrast, negative parental styles correlated positively with behaviors that support bullying (r = 0.12, p < 0.01) and instances of family violence (r = 0.62, p < 0.01). Basic empathy negatively predicted behaviors that promote bullying (ß = -0.098, p < 0.01) and positively predicted protective behaviors toward victims (ß = 0.249, p < 0.001). Furthermore, family violence weakened the positive effects of positive parental styles on both empathy (ß = -0.075, p < 0.001) and protective behaviors (ß = -0.025, p < 0.01). Conclusion: The findings indicate that positive parental styles indirectly promote adolescents' victim protector behaviors by enhancing their basic empathy, underscoring the importance of emotional cultivation. Meanwhile, family violence weakens the positive impact of these parental styles on basic empathy and protective behaviors, harming adolescents' emotional security and behavioral norms.

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Developing effective vaccines is necessary in combating new virus pandemics. For HIV and SARS-CoV-2, the induction of neutralizing antibodies (NAb) is important for vaccine protection; however, the exact mechanisms underlying protection require further study. Recent data emphasize that even Abs that do not exhibit neutralizing activity may contribute to immune defense. Abs exhibiting this function may counter virus mutations, which are acquired to escape from NAbs, and therefore, broaden the protective Ab response induced by vaccination. However, the steps leading to Ab Fc-mediated inhibition are complex. How can these functions be measured in vitro? What inhibitory assay is the most physiologically relevant at mimicking effective in vivo protection? This review provides a comprehensive update on the current knowledge gaps on the Ab Fc-mediated functions involved in HIV and SARS-CoV-2 protection. Understanding the inhibitory effects of these Abs is vital for designing the next generation of protective HIV and SARS-CoV-2 vaccines.

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Bisphenol A (BPA), a common endocrine disruptor, has shown cardiovascular toxicity in several epidemiological studies, as well as in vivo and in vitro experimental studies. However, the related adverse outcome pathway (AOP) of BPA toxicity remains unraveled. This study aimed to develop an AOP for the cardiac toxicity of BPA through bioinformatics analysis. The interactions among BPA, genes, phenotypes, and cardiac toxicity were retrieved from several databases, including the Comparative Toxicogenomics Database, Computational Toxicology, DisGeNet, and MalaCards. The target genes and part of target phenotypes were obtained by Venn analysis and literature screening. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed for target genes by using the DAVID online analysis tool to obtain other target phenotypes. AOP hypotheses from BPA exposure to heart disease were established and evaluated comprehensively by a quantitative weight of evidence (QWOE) method. The target genes included ESR2, MAPK1, TGFB1, and ESR1, and the target phenotypes included heart contraction, cardiac muscle contraction, cellular Ca2+ homeostasis, cellular metabolic process, heart development, etc. Overall, the AOP of BPA cardiac toxicity was deduced to be as follows. Initially, BPA bound with ERα/ß and then activated the MAPK, AKT, and IL-17 signaling pathways, leading to Ca2+ homeostasis disorder and increased inflammatory response. Subsequently, cardiac function was impaired, causing coronary heart disease, arrhythmia, cardiac dysplasia, and other heart diseases. According to the Bradford-Hill causal considerations, the score of AOP by QWOE was 69, demonstrating a moderate confidence and providing clues on cardiotoxicity-assessment procedure and further studies on BPA.

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The pseudomagnetic field effect may offer unique opportunities for the emergence of intriguing phenomena. To date, investigations into pseudomagnetic field effects on phonons have been limited to sound waves in metamaterials. The revelation of this exotic effect on the atomic vibration of natural materials remains elusive. Our simulations of twisted graphene nanoribbons reveal well-defined Landau spectra and sublattice polarization of phonon states, mimicking the behavior of Dirac Fermions in magnetic fields. Both valley-specified helical edge currents and snake orbits are obtained. Analysis of dynamics indicates that phonon Landau states have extended lifetimes, which are crucial for the realization of Landau-level lasing. Our findings demonstrate the occurrence of the phonon pseudomagnetic field effect in natural materials, which has important implications for the mechanical tuning of phonon quantum states at the atomic scale.

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Spinal cord injury (SCI) triggers microglial/monocytes activation with distinct pro-inflammatory or inflammation-resolving phenotypes, which potentiate tissue damage or facilitate functional repair, respectively. The major integrin Mac-1 (CD11b/CD18), a heterodimer consisting of CD11b and CD18 chains, is expressed in multiple immune cells of the myeloid lineage. Here, we examined the effects of CD11b gene ablation in neuroinflammation and functional outcomes after SCI. qPCR analysis of C57BL/6 female mice showed upregulation of CD11b mRNA starting from 1 d after injury, which persisted up to 28 d. CD11b knockout (KO) mice and their wildtype littermates were subjected to moderate SCI. At 1 d post-injury, qPCR showed increased expression of genes involved with inflammation-resolving processes in CD11b KO mice. Flow cytometry analysis of CD45intLy6C-CX3CR1+ microglia, CD45hiLy6C+Ly6G- monocytes, and CD45hiLy6C+Ly6G+ neutrophils revealed significantly reduced cell counts as well as reactive oxygen species (ROS) production in CD11b KO mice at d3 post-injury. Further examination with NanoString and RNA-seq showed upregulation of pro-inflammatory genes, but downregulation of the ROS pathway. Importantly, CD11b KO mice exhibited significantly improved locomotor function, reduced cutaneous mechanical/thermal hypersensitivity, and limited tissue damage at 8 weeks post-injury. Collectively, our data suggest an important role for CD11b in regulating tissue inflammation and functional outcome following SCI.

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This study addresses the relationship between platelet count and 30-day in-hospital mortality in End-Stage Kidney Disease (ESRD) patients in the intensive care unit (ICU), a topic with limited existing evidence. Utilizing data from the US eICU-CRD v2.0 database (2014-2015), a retrospective cohort study was conducted involving 3700 ICU ESRD patients. We employed binary logistic regression, smooth curve fitting, and subgroup analyses to explore the association between platelet count and 30-day in-hospital mortality. The 30-day in-hospital mortality rate was 13.27% (491/3700), with a median platelet count of 188 × 109/L. After adjusting for covariates, we observed a relationship between platelet count and 30-day in-hospital mortality (OR = 0.98, 95% CI 0.97, 0.99). Subgroup analyses supported these findings. More importantly, a nonlinear association was detected, with an inflection point at 222 × 109/L. The effect sizes (OR) on the left and right sides of the inflection point were 0.94 (0.92, 0.96) and 1.03 (1.00, 1.05), respectively. The most significant finding of this study is the revelation of a nonlinear relationship between baseline platelet count and 30-day in-hospital mortality in ICU patients with ESRD. This discovery explicitly suggests that when ESRD patients are admitted to the ICU, a platelet level closer to 222 × 109/L may predict a lower 30-day in-hospital mortality risk.

Assuntos