Higher tumor mutational burden is associated with inferior outcomes among pediatric patients with neuroblastoma.

INTRODUCTION: Neuroblastoma is a pediatric malignancy with heterogeneous clinical outcomes. Our aim was to identify prognostic genetic markers for patients with neuroblastoma, who were treated with the Taiwan Pediatric Oncology Group (TPOG) neuroblastoma N2002 protocol, to improve risk stratification and inform treatment. METHODS: Our analysis was based on 53 primary neuroblastoma specimens, diagnosed pre-chemotherapy, and 11 paired tumor relapse specimens. Deep sequencing of 113 target genes was performed using a custom panel. Multiplex ligation-dependent probe amplification was performed to identify clinical outcomes related to copy-number variations. RESULTS: We identified 128 variations associated with survival, with the number of variations being higher in the relapse than that in the diagnostic specimen (p = .03). The risk of event and mortality was higher among patients with a tumor mutational burden ≥10 than that in patients with a lower burden (p < .0001). Multivariate analysis identified tumor mutational burden, MYCN amplification, and chromosome 3p deletion as significant prognostic factors, independent of age at diagnosis, sex, and tumor stage. The 5-year event-free survival and overall survival rate was lower among patients with high tumor burden than in patients with low tumor burden. Furthermore, there was no survival of patients with an ALK F1147L variation at 5 years after diagnosis. CONCLUSIONS: Genome sequencing to determine the tumor mutational burden and ALK variations can improve the risk classification of neuroblastoma and inform treatment.

Air Pollution Exposures and Child Executive Function: A U.S. Multi-Cohort Study.

BACKGROUND: Executive function, which develops rapidly in childhood, enables problem solving, focused attention, and planning. Animal models describe executive function decrements associated with ambient air pollution exposure, but epidemiologic studies are limited. METHODS: We examined associations between early childhood air pollution exposure and school-aged executive function in 1,235 children from three U.S. pregnancy cohorts in the ECHO-PATHWAYS Consortium. We derived point-based residential exposures to ambient particulate matter ≤2.5µm in aerodynamic diameter (PM2.5) and nitrogen dioxide (NO2), and ozone (O3) at ages 0-4 years from spatiotemporal models with a 2-week resolution. We assessed executive function across three domains -- cognitive flexibility, working memory, and inhibitory control -- using performance-based measures and calculated a composite score quantifying overall performance. We fitted linear regressions to assess air pollution - child executive function associations, adjusting for sociodemographic characteristics, maternal mental health, and health behaviors, and examined modification by child sex, maternal education, and neighborhood educational opportunity. RESULTS: In the overall sample, we found hypothesized inverse associations in crude but not adjusted models. Modified associations between NO2 exposure and working memory by neighborhood education opportunity were present (P interaction = 0.05), with inverse associations more pronounced in the "High" and "Very high" categories. Associations of interest did not differ by child sex or maternal education. CONCLUSIONS: This work contributes to the evolving science regarding early-life environmental exposures and child development. There remains a need for continued exploration in future research endeavors, to elucidate the complex interplay between natural environment and social determinants influencing child neurodevelopment.

Prenatal exposure to polycyclic aromatic hydrocarbons and executive functions at school age: Results from a combined cohort study.

BACKGROUND: Executive functions develop rapidly in childhood, enabling problem-solving, focused attention, and planning. Exposures to environmental toxicants in pregnancy may impair healthy executive function development in children. There is increasing concern regarding polycyclic aromatic hydrocarbons (PAHs) given their ability to transfer across the placenta and the fetal blood-brain barrier, yet evidence from epidemiological studies is limited. METHODS: We examined associations between prenatal PAH exposure and executive functions in 814 children of non-smoking mothers from two U.S. cohorts in the ECHO-PATHWAYS Consortium. Seven mono-hydroxylated PAH metabolites were measured in mid-pregnancy urine and analyzed individually and as mixtures. Three executive function domains were measured at age 8-9: cognitive flexibility, working memory, and inhibitory control. A composite score quantifying overall performance was further calculated. We fitted linear regressions adjusted for socio-demographics, maternal health behaviors, and psychological measures, and examined modification by child sex and stressful life events in pregnancy. Bayesian kernel machine regression was performed to estimate the interactive and overall effects of the PAH mixture. RESULTS: The results from primary analysis of linear regressions were generally null, and no modification by child sex or maternal stress was indicated. Mixture analyses suggested several pairwise interactions between individual PAH metabolites in varied directions on working memory, particularly interactions between 2/3/9-FLUO and other PAH metabolites, but no overall or individual effects were evident. CONCLUSION: We conducted a novel exploration of PAH-executive functions association in a large, combined sample from two cohorts. Although findings were predominantly null, the study carries important implications for future research and contributes to evolving science regarding developmental origins of diseases.

Origin of Interfacial Orbital Reconstruction in Perovskite Superlattices.

The competition between on-site electronic correlation and local crystal field stands out as a captivating topic in research. However, its physical ramifications often get overshadowed by influences of strong periodic potential and orbital hybridization. The present study reveals this competition may become more pronounced or even dominant in two-dimensional systems, driven by the combined effects of dimensional confinement and orbital anisotropy. This leads to electronic orbital reconstruction in certain perovskite superlattices or thin films. To explore the emerging physics, we investigate the interfacial orbital disorder-order transition with an effective Hamiltonian and how to modulate this transition through strains.

Analysis of approved dental teaching projects in the teaching practice research program in 8 dental schools of Taiwan from 2018 to 2023.

Background/purpose: The teaching practice research program was initiated by Taiwan's Ministry of Education in 2018 to improve medical teaching quality. This study analyzed dental teaching projects conducted under this program from 2018 to 2023. Materials and methods: Data of submitted and approved medical (including dental) teaching projects from 2018 to 2023 were obtained from the annual reports released by the program committee. The annual passing rates were calculated by dividing the number of approved dental teaching projects by the total number of approved medical teaching projects in the category of medical and healthcare sciences in a particular year. The 24 approved dental teaching projects were reviewed, classified into different topics in the dental field, and then reported. Results: There were 24 approved dental teaching projects out of a total of 822 approved medical teaching projects from 2018 to 2023. The annual passing rates increased gradually from 2018 (1.4 %) to 2022 (3.9 %) and 2023 (3.8 %) with an overall mean passing rate of 2.9 % over a period of 6 years. Of the 24 approved dental teaching projects, digital dentistry was the most common teaching research topic (9 projects), followed by new teaching models (7 projects), 3D technology (3 projects), endodontics (3 projects), dental histology (one project), and evidence-based method (one project). Conclusion: Digital dentistry and new teaching models were the two predominant dental teaching research topics, suggesting that both are the modern trends in the dental education. However, the dental teaching research projects are still very limited in 8 Taiwanese dental schools.

Associations of prenatal ambient air pollution exposures with asthma in middle childhood.

We examined associations between prenatal fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) exposures and child respiratory outcomes through age 8-9 years in 1279 ECHO-PATHWAYS Consortium mother-child dyads. We averaged spatiotemporally modeled air pollutant exposures during four fetal lung development phases: pseudoglandular (5-16 weeks), canalicular (16-24 weeks), saccular (24-36 weeks), and alveolar (36+ weeks). We estimated adjusted relative risks (RR) for current asthma at age 8-9 and asthma with recent exacerbation or atopic disease, and odds ratios (OR) for wheezing trajectories using modified Poisson and multinomial logistic regression, respectively. Effect modification by child sex, maternal asthma, and prenatal environmental tobacco smoke was explored. Across all outcomes, 95% confidence intervals (CI) included the null for all estimates of associations between prenatal air pollution exposures and respiratory outcomes. Pseudoglandular PM2.5 exposure modestly increased risk of current asthma (RRadj = 1.15, 95% CI: 0.88-1.51); canalicular PM2.5 exposure modestly increased risk of asthma with recent exacerbation (RRadj = 1.26, 95% CI: 0.86-1.86) and persistent wheezing (ORadj = 1.28, 95% CI: 0.86-1.89). Similar findings were observed for O3, but not NO2, and associations were strengthened among mothers without asthma. While not statistically distinguishable from the null, trends in effect estimates suggest some adverse associations of early pregnancy air pollution exposures with child respiratory conditions, warranting confirmation in larger samples.

Prenatal polycyclic aromatic hydrocarbon exposure and asthma at age 8-9 years in a multi-site longitudinal study.

BACKGROUND AND AIM: Studies suggest prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) may influence wheezing or asthma in preschool-aged children. However, the impact of prenatal PAH exposure on asthma and wheeze in middle childhood remain unclear. We investigated these associations in socio-demographically diverse participants from the ECHO PATHWAYS multi-cohort consortium. METHODS: We included 1,081 birth parent-child dyads across five U.S. cities. Maternal urinary mono-hydroxylated PAH metabolite concentrations (OH-PAH) were measured during mid-pregnancy. Asthma at age 8-9 years and wheezing trajectory across childhood were characterized by caregiver reported asthma diagnosis and asthma/wheeze symptoms. We used logistic and multinomial regression to estimate odds ratios of asthma and childhood wheezing trajectories associated with five individual OH-PAHs, adjusting for urine specific gravity, various maternal and child characteristics, study site, prenatal and postnatal smoke exposure, and birth year and season in single metabolite and mutually adjusted models. We used multiplicative interaction terms to evaluate effect modification by child sex and explored OH-PAH mixture effects through Weighted Quantile Sum regression. RESULTS: The prevalence of asthma in the study population was 10%. We found limited evidence of adverse associations between pregnancy OH-PAH concentrations and asthma or wheezing trajectories. We observed adverse associations between 1/9-hydroxyphenanthrene and asthma and persistent wheeze among girls, and evidence of inverse associations with asthma for 1-hydroxynathpthalene, which was stronger among boys, though tests for effect modification by child sex were not statistically significant. CONCLUSIONS: In a large, multi-site cohort, we did not find strong evidence of an association between prenatal exposure to PAHs and child asthma at age 8-9 years, though some adverse associations were observed among girls.

Male Carrier of X-Linked Adrenal Leukodystrophy Due to 47, XXY Karyotype.

This case report studies a 12-year-old boy with a family history of X-linked adrenal leukodystrophy and his 8-year-old younger brother.

Classification Prediction of Alzheimer's Disease and Vascular Dementia Using Physiological Data and ECD SPECT Images.

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common forms of dementia. However, their neuropsychological and pathological features often overlap, making it difficult to distinguish between AD and VaD. In addition to clinical consultation and laboratory examinations, clinical dementia diagnosis in Taiwan will also include Tc-99m-ECD SPECT imaging examination. Through machine learning and deep learning technology, we explored the feasibility of using the above clinical practice data to distinguish AD and VaD. We used the physiological data (33 features) and Tc-99m-ECD SPECT images of 112 AD patients and 85 VaD patients in the Taiwanese Nuclear Medicine Brain Image Database to train the classification model. The results, after filtering by the number of SVM RFE 5-fold features, show that the average accuracy of physiological data in distinguishing AD/VaD is 81.22% and the AUC is 0.836; the average accuracy of training images using the Inception V3 model is 85% and the AUC is 0.95. Finally, Grad-CAM heatmap was used to visualize the areas of concern of the model and compared with the SPM analysis method to further understand the differences. This research method can quickly use machine learning and deep learning models to automatically extract image features based on a small amount of general clinical data to objectively distinguish AD and VaD.

Integration or fragmentation: the arrow of China's lithium product development.

Lithium is an indispensable resource for the next generation of clean technology. Promoting the development of lithium industry has become a global consensus, with China being no exception. The development process involves not only the growth and degeneration of lithium products but also the path-dependency issues arising from resources and technology. This study, based on the perspective of product space structure, constructs China's lithium product network to study its pattern evolution and predict the development direction. Then, according to the current situation and pattern evolution trends, potential advantageous lithium products and advantage-degraded lithium products are identified, and tactics for expanding chains and breaking chains are formulated for them, presenting strategies for the integrated and fragmentated development of China's lithium products. This aims to steer China's lithium products towards a more orderly and closely interconnected direction, representing the arrow of development for China's lithium products.

Deconstructing the Dimensions of Mycobiome Fingerprints in Luohandu Cave, Guilin, Southern China.

Subterranean karst caves are windows into the terrestrial subsurface to deconstruct the dimensions of mycobiome fingerprints. However, impeded by the constraints of remote locations, the inaccessibility of specimens and technical limitations, the mycobiome of subterranean karst caves has remained largely unknown. Weathered rock and sediment samples were collected from Luohandu cave (Guilin, Southern China) and subjected to Illumina Hiseq sequencing of ITS1 genes. A total of 267 known genera and 90 known orders in 15 phyla were revealed in the mycobiomes. Ascomycota dominated all samples, followed by Basidiomycota and Mortierellomycota. The sediments possessed the relatively highest alpha diversity and were significantly different from weathered rocks according to the diversity indices and richness metrics. Fifteen families and eight genera with significant differences were detected in the sediment samples. The Ca/Mg ratio appeared to significantly affect the structure of the mycobiome communities. Ascomycota appeared to exert a controlling influence on the mycobiome co-occurrence network of the sediments, while Ascomycota and Basidiomycota were found to be the main phyla in the mycobiome co-occurrence network of weathered rocks. Our results provide a more comprehensive dimension to the mycobiome fingerprints of Luohandu cave and a new window into the mycobiome communities and the ecology of subterranean karst cave ecosystems.

Diselenophosphate Ligands as a Surface Engineering Tool in PdH-Doped Silver Superatomic Nanoclusters.

The first hydride-doped Pd/Ag superatoms stabilized by selenolates are reported: [PdHAg19(dsep)12] [dsep = Se2P(OiPr)2] 1 and [PdHAg20(dsep)12]+ 2. 1 was derived from the targeted transformation of [PdHAg19(dtp)12] [dtp = S2P(OiPr)2] by ligand exchange, whereas 2 was obtained from the addition of trifluoroacetic acid to 1, resulting in a symmetric redistribution of the capping silver atoms. The transformations are all achieved while retaining an 8-electron superatomic configuration. VT-NMR attests to the good stability of the NCs in solution, and single-crystal X-ray diffraction reveals the crucial role that the interstitial hydride plays in directing the position of the capping silver atoms. The total structures are reported alongside their electronic and optical properties. 1 and 2 are phosphorescent with a lifetime of 73 and 84 µs at 77 K, respectively. The first antibacterial activity data for superatomic bimetallic Pd/Ag nanoclusters are also reported.

Long-term ozone exposure and lung function in middle childhood.

BACKGROUND: Ozone (O3) exposure interrupts normal lung development in animal models. Epidemiologic evidence further suggests impairment with higher long-term O3 exposure across early and middle childhood, although study findings to date are mixed and few have investigated vulnerable subgroups. METHODS: Participants from the CANDLE study, a pregnancy cohort in Shelby County, TN, in the ECHO-PATHWAYS Consortium, were included if children were born at gestational age >32 weeks, completed a spirometry exam at age 8-9, and had a valid residential history from birth to age 8. We estimated lifetime average ambient O3 exposure based on each child's residential history from birth to age 8, using a validated fine-resolution spatiotemporal model. Spirometry was performed at the age 8-9 year study visit to assess Forced Expiratory Volume in the first second (FEV1) and Forced Vital Capacity (FVC) as primary outcomes; z-scores were calculated using sex-and-age-specific reference equations. Linear regression with robust variance estimators was used to examine associations between O3 exposure and continuous lung function z-scores, adjusted for child, sociodemographic, and home environmental factors. Potential susceptible subgroups were explored using a product term in the regression model to assess effect modification by child sex, history of bronchiolitis in infancy, and allergic sensitization. RESULTS: In our sample (n = 648), O3 exposure averaged from birth to age 8 was modest (mean 26.6 [SD 1.1] ppb). No adverse associations between long-term postnatal O3 exposure were observed with either FEV1 (ß = 0.12, 95% CI: -0.04, 0.29) or FVC (ß = 0.03, 95% CI: -0.13, 0.19). No effect modification by child sex, history of bronchiolitis in infancy, or allergic sensitization was detected for associations with 8-year average O3. CONCLUSIONS: In this sample with low O3 concentrations, we did not observe adverse associations between O3 exposures averaged from birth to age 8 and lung function in middle childhood.

Rapid conversion of porcine pluripotent stem cells into macrophages with chemically defined conditions.

A renewable source of porcine macrophages derived from pluripotent stem cells (PSCs) would be a valuable alternative to primary porcine alveolar macrophages (PAMs) in the research of host-pathogen interaction mechanisms. We developed an efficient and rapid protocol, within 11 days, to derive macrophages from porcine PSCs (pPSCs). The pPSC-derived macrophages (pPSCdMs) exhibited molecular and functional characteristics of primary macrophages. The pPSCdMs showed macrophage-specific surface protein expression and macrophage-specific transcription factors, similar to PAMs. The pPSCdMs also exhibited the functional characteristics of macrophages, such as endocytosis, phagocytosis, porcine respiratory and reproductive syndrome virus infection and the response to lipopolysaccharide stimulation. Furthermore, we performed transcriptome sequencing of the whole differentiation process to track the fate transitions of porcine PSCs involved in the signaling pathway. The activation of transforming growth factor beta signaling was required for the formation of mesoderm and the inhibition of the transforming growth factor beta signaling pathway at the hematopoietic endothelium stage could enhance the fate transformation of hematopoiesis. In summary, we developed an efficient and rapid protocol to generate pPSCdMs that showed aspects of functional maturity comparable with PAMs. pPSCdMs could provide a broad prospect for the platforms of host-pathogen interaction mechanisms.

Quantitative Ensemble Interpretation of Membrane Paramagnetic Relaxation Enhancement (mPRE) for Studying Membrane-Associated Intrinsically Disordered Proteins.

An understanding of the functional role played by a membrane-associated intrinsically disordered protein (IDP) requires characterization of its heterogeneous conformations as well as its poses relative to the membranes, which is of great interest but technically challenging. Here, we explore the membrane paramagnetic relaxation enhancement (mPRE) for constructing ensembles of IDPs that dynamically associate with membrane mimetics incorporating spin-labeled lipids. To accurately interpret the mPRE Γ2 rates, both the dynamics of IDPs and spin probe molecules are taken into account, with the latter described by a weighted three-dimensional (3D) grid model built based on all-atom simulations. The IDP internal conformations, orientations, and immersion depths in lipid bilayers are comprehensively optimized in the Γ2-based ensemble modeling. Our approach is tested and validated on the example of POPG bicelle-bound disordered cytoplasmic domain of CD3ε (CD3εCD), a component of the T-cell receptor (TCR) complex. The mPRE-derived CD3εCD ensemble provides new insights into the IDP-membrane fuzzy association, in particular for the tyrosine-based signaling motif that plays a critical role in TCR signaling. The comparative analysis of the ensembles for wild-type CD3εCD and mutants that mimic the mono- and dual-phosphorylation effects suggests a delicate membrane regulatory mechanism for activation and inhibition of the TCR activity.

Engineering of redox partners and cofactor NADPH supply of CYP68JX for efficient steroid two-step ordered selective hydroxylation activity.

CYP68JX, a P450 hydroxylase, derived from Colletotrichum lini ST-1 is capable of biotransforming dehydroepiandrosterone (DHEA) to 3ß,7α,15α-trihydroxy-5-androstene-17-one (7α,15α-diOH-DHEA). Redox partners and cofactor supply are important factors affecting the catalytic activity of CYP68JX. In this study, the heterologous expression of CYP68JX in Saccharomyces cerevisiae BY4741 was realized resulting in a 17.1% target product yield. In order to increase the catalytic efficiency of CYP68JX in S. cerevisiae BY4741, a complete cytochrome P450 redox system was constructed. Through the combination of CYP68JX and heterologous CPRs, the yield of the target product 7α,15α-diOH-DHEA in CYP68JX recombinant system was increased to 37.8%. Furthermore, by adding NADPH coenzyme precursor tryptophan of 40 mmol/L and co-substrate fructose of 20 g/L during the conversion process, the catalytic efficiency of CYP68JX was further improved, the target product yield reached 57.9% which was 3.39-fold higher than initial yield. Overall, this study provides a reference for improving the catalytic activity of P450s.

[Application of single-arm objective performance criteria/performance goal in acupuncture-moxibustion clinical trials].

Due to various constraints, such as clinical implementation conditions and unique characteristics of acupuncture-moxibustion, some randomized controlled trials (RCTs) of acupuncture-moxibustion still suffer from relatively low quality and limited applicability. The single-arm objective performance criteria/performance goal can be considered as an ideal supplementary and alternative research approach to RCTs. In this paper, the feasibility of applying the single-arm objective performance criteria/performance goal in acupuncture-moxibustion clinical research is explored from the limitations of conducting acupuncture-moxibustion RCTs, the principles, the essential design considerations and key statistical steps. In addition, illustrative examples are provided. The objective is to offer insights into resolving practical difficulties in acupuncture-moxibustion clinical research.

Base-Mediated α-gem-Difluoroalkenylations of Aldehydes and Ketones.

Herein, we present a base-mediated nucleophilic substitution reaction of α-trifluoromethylstyrenes with simple silyl enol ethers, enabling the efficient synthesis of carbonyl-substituted gem-difluoroalkenes. The merit of this protocol is exhibited by its mild reaction conditions, broad substrate scope, and scalable preparation. Notably, this method demonstrates its applicability for late-stage functionalization of structurally complex molecules. Moreover, we illustrate that the resulting products can serve as valuable precursors for the synthesis of diverse medicinally relevant compounds.

Integrated analysis of the ubiquitination mechanism reveals the specific signatures of tissue and cancer.

BACKGROUND: Ubiquitination controls almost all cellular processes. The dysregulation of ubiquitination signals is closely associated with the initiation and progression of multiple diseases. However, there is little comprehensive research on the interaction and potential function of ubiquitination regulators (UBRs) in spermatogenesis and cancer. METHODS: We systematically characterized the mRNA and protein expression of UBRs across tissues and further evaluated their roles in testicular development and spermatogenesis. Subsequently, we explored the genetic alterations, expression perturbations, cancer hallmark-related pathways, and clinical relevance of UBRs in pan-cancer. RESULTS: This work reveals heterogeneity in the expression patterns of UBRs across tissues, and the expression pattern in testis is the most distinct. UBRs are dynamically expressed during testis development, which are critical for normal spermatogenesis. Furthermore, UBRs have widespread genetic alterations and expression perturbations in pan-cancer. The expression of 79 UBRs was identified to be closely correlated with the activity of 32 cancer hallmark-related pathways, and ten hub genes were screened for further clinical relevance analysis by a network-based method. More than 90% of UBRs can affect the survival of cancer patients, and hub genes have an excellent prognostic classification for specific cancer types. CONCLUSIONS: Our study provides a comprehensive analysis of UBRs in spermatogenesis and pan-cancer, which can build a foundation for understanding male infertility and developing cancer drugs in the aspect of ubiquitination.