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Abstract Cholinergic dysfunction has been implicated in the pathophysiology of psychosis and psychiatric disorders such as schizophrenia, depression, and bipolar disorder. The basal forebrain (BF) cholinergic nuclei, defined as cholinergic cell groups Ch1-3 and Ch4 (Nucleus Basalis of Meynert; NBM), provide extensive cholinergic projections to the rest of the brain. Here, we examined microstructural neuroimaging measures of the cholinergic nuclei in patients with untreated psychosis (~31 weeks of psychosis, 0.05). Case-control differences in qT1 and AxD were observed in the Ch1-3, with increased qT1 (reflecting reduced myelin content) and AxD (reflecting reduced axonal integrity). We found clinical correlates between left NBM qT1 with manic symptom severity, and AxD with negative symptom burden in FEP. Intracortical and subcortical myelin maps were derived and correlated with BF myelin. BF-cortical and BF-subcortical myelin correlations demonstrate known projection patterns from the BF. Using data from the Allen Human Brain Atlas, cholinergic nuclei showed significant enrichment for schizophrenia and depression-related genes. Cell-type specific enrichment indicated enrichment for cholinergic neuron markers as expected. Further relating the neuroimaging correlations to transcriptomics demonstrated links with cholinergic receptor genes and cell type markers of oligodendrocytes and cholinergic neurons, providing biological validity to the measures. These results provide genetic, neuroimaging, and clinical evidence for cholinergic dysfunction in schizophrenia.

This research introduces an advanced method for predicting seismic responses and hysteresis curves of instrumented bridge piers and bearings under various loading conditions, leaning solely on a single deep learning architecture and the same hyperparameters tuning. Test specimens are subjected to ground accelerations including vertical seismic loads and axial forces. To accurately capture peak values, particularly on the negative side of the hysteresis loop (unloading region), the model employs a stacked deep architecture. A key component to overcome the challenges is the self-attention-Mamba-driven transformer layer, which enhances the model's ability to capture long-range dependencies in seismic data. This layer works in conjunction with other deep learning techniques to ensure robust and precise predictions. Implemented with Python's Keras functional API, the model processes inputs like ground accelerations, actuator loads, effective height, moment of inertia, and superstructure mass. The model is evaluated with a dataset of 95 real-time hybrid simulation (RTHS) tests for lead rubber bearings, 29 RTHS tests for bridge piers, and 17 cyclic tests (10 fast and 7 slow). Extensive hyperparameter tuning demonstrates the model's proficiency to capture hysteresis and residual deformations accurately. Achieving an impressive correlation with experimentally measured values, ranging from 88.1 to 98.9%, and a reasonable dissipated energy error ratio are notable. The deep learning model reduces the need for additional tests, offering time and cost savings, and provides rapid, and accurate insights into bridge behavior. This supports timely and precise bridge design and aids decision-makers during emergencies., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The rich set of mechanoreceptors found in human skin 1,2 offers a versatile engineering interface for transmitting information and eliciting perceptions 3,4 , potentially serving a broad range of applications in patient care 5 and other important industries 6,7 . Targeted multisensory engagement of these afferent units, however, faces persistent challenges, especially for wearable, programmable systems that need to operate adaptively across the body 8-11 . Here we present a miniaturized electromechanical structure that, when combined with skin as an elastic, energy-storing element, supports bistable, self-sensing modes of deformation. Targeting specific classes of mechanoreceptors as the basis for distinct, programmed sensory responses, this haptic unit can deliver both dynamic and static stimuli, directed as either normal or shear forces. Systematic experimental and theoretical studies establish foundational principles and practical criteria for low-energy operation across natural anatomical variations in the mechanical properties of human skin. A wireless, skin-conformable haptic interface, integrating an array of these bistable transducers, serves as a high-density channel capable of rendering input from smartphone-based 3D scanning and inertial sensors. Demonstrations of this system include sensory substitution designed to improve the quality of life for patients with visual and proprioceptive impairments., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Disruptions in pericyte and endothelial cell communication can compromise the integrity of the blood-brain barrier (BBB), leading to neurovascular dysfunction and the development of neurological disorders. However, the evaluation of microvessel RNAs has been limited to tissue homogenates, with spatial visualization only available for protein targets. The aim of the present study is the development of an innovative microvessel isolation technique that is RNA-friendly for the purpose of coupling with in situ hybridization RNAscope analysis. RNA-friendly microvessel isolation combined with RNAscope analysis enables the visualization of cell-specific RNA within the spatial and histological context of the BBB. Using this approach, we have gained valuable insights into the structural and functional differences associated with the microvessels of 5xFAD mice, a mouse model of Alzheimer's disease (AD). RNAscope analysis revealed a decrease in pericytes from microvessels isolated from 5xFAD mice in comparison to wild-type mice. Additionally, the microvessels of 5xFAD mice exhibited an increase in TYRO protein tyrosine kinase binding protein (TYROBP) mRNA expression. These findings significantly advance our understanding of neurovascular interactions and hold great promise for guiding the development of targeted therapeutic interventions. This innovative approach enables visualization of cell RNA while preserving the spatial and histological context of the BBB, shedding light on the mechanisms underlying neurovascular unit communication., (© 2024. The Author(s).)

Maternal nutrition significantly influences fetal development and postnatal outcomes. This study investigates the impact of maternal overfeeding during mid to late pregnancy on gene expression in the round and sirloin muscles of Hanwoo neonatal calves. Eight cows were assigned to either a control group receiving standard nutrition (100%) or a treated group receiving overnutrition (150%). After birth, tissue samples from the round and sirloin muscles of neonatal calves were collected and subjected to RNA sequencing to assess differentially expressed genes (DEGs). RNA sequencing identified 43 DEGs in round muscle and 15 in sirloin muscle, involving genes related to myogenesis, adipogenesis, and energy regulation. Key genes, including PPARGC1A, THBS1, CD44, JUND, CNN1, ENAH, and RUNX1, were predominantly downregulated. Gene ontology (GO) enrichment analyses revealed terms associated with muscle development, such as "biological regulation," "cellular process," and "response to stimulus." Protein-protein interaction networks highlighted complex interactions among DEGs. Random Forest analysis identified ARC, SLC1A5, and GNPTAB as influential genes for distinguishing between control and treated groups. Overall, maternal overnutrition during mid-to-late pregnancy results in the downregulation of genes involved in muscle development and energy metabolism in neonatal Hanwoo calves. These findings provide insights into the molecular effects of maternal nutrition on muscle development., (© 2024. The Author(s).)

Dyskalemia is a common electrolyte abnormality. Since dyskalemia can cause fatal arrhythmias and cardiac arrest in severe cases, it is crucial to monitor serum potassium (K + ) levels on time. We developed deep learning models to detect hyperkalemia (K +  ≥ 5.5 mEq/L) and hypokalemia (K +  < 3.5 mEq/L) from electrocardiograms (ECGs), which are noninvasive and can be quickly measured. The retrospective cohort study was conducted at two hospitals from 2006 to 2020. The training set, validation set, internal testing cohort, and external validation cohort comprised 310,449, 15,828, 23,849, and 130,415 ECG-K + samples, respectively. Deep learning models demonstrated high diagnostic performance in detecting hyperkalemia (AUROC 0.929, 0.912, 0.887 with sensitivity 0.926, 0.924, 0.907 and specificity 0.706, 0.676, 0.635 for 12-lead, limb-lead, lead I ECGs) and hypokalemia (AUROC 0.925, 0.896, 0.885 with sensitivity 0.912, 0.896, 0.904 and specificity 0.790, 0.734, 0.694) in the internal testing cohort. The group predicted to be positive by the hyperkalemia model showed a lower 30-day survival rate compared to the negative group (p < 0.001), supporting the clinical efficacy of the model. We also compared the importance of ECG segments (P, QRS, and T) on dyskalemia prediction of the model for interpretability. By applying these models in clinical practice, it will be possible to diagnose dyskalemia simply and quickly, thereby contributing to the improvement of patient outcomes., (© 2024. The Author(s).)

Alternative cleavage and polyadenylation within introns (intronic APA) generate shorter mRNA isoforms; however, their physiological significance remains elusive. In this study, we developed a comprehensive workflow to analyze intronic APA profiles using the mammalian target of rapamycin (mTOR)-regulated transcriptome as a model system. Our investigation revealed two contrasting effects within the transcriptome in response to fluctuations in cellular mTOR activity: an increase in intronic APA for a subset of genes and a decrease for another subset of genes. The application of this workflow to RNA-seq data from The Cancer Genome Atlas demonstrated that this dichotomous intronic APA pattern is a consistent feature in transcriptomes across both normal tissues and various cancer types. Notably, our analyses of protein length changes resulting from intronic APA events revealed two distinct phenomena in proteome programming: a loss of functional domains due to significant changes in protein length or minimal alterations in C-terminal protein sequences within unstructured regions. Focusing on conserved intronic APA events across 10 different cancer types highlighted the prevalence of the latter cases in cancer transcriptomes, whereas the former cases were relatively enriched in normal tissue transcriptomes. These observations suggest potential, yet distinct, roles for intronic APA events during pathogenic processes and emphasize the abundance of protein isoforms with similar lengths in the cancer proteome. Furthermore, our investigation into the isoform-specific functions of JMJD6 intronic APA events supported the hypothesis that alterations in unstructured C-terminal protein regions lead to functional differences. Collectively, our findings underscore intronic APA events as a discrete molecular signature present in both normal tissues and cancer transcriptomes, highlighting the contribution of APA to the multifaceted functionality of the cancer proteome., (© 2024. The Author(s).)

Background: We aimed to investigate the association between developmental screening before 24 months of age and neurodevelopmental disorders (NDDs) at 4-6 years of age., Methods: We included 922,899 newborn born between 2014 and 2016 registered in National Health Insurance Service (NHIS). Developmental screening was administered at 9-12 and 18-24 months old with the Korean Developmental Screening Test for Infants & Children (K-DST). Diagnoses of NDDs was based on the World Health Organization's International Classification of Diseases, Tenth Revision (ICD-10), provided by the NHIS database., Results: Among 637,277 individuals who underwent screening at 9-12 and 18-24 months, Screen-positivity (defined as summed score < -2 standard deviation) for gross motor domain at 9-12 months was significantly associated with the incidence of autism spectrum disorder (aHR, 2.24; 95% CI, 1.80-2.80) and cerebral palsy (aHR, 4.81; 95% CI, 3.62-6.38). Screening positive at language domain at 18-24 months old was associated with autism spectrum disorder (aHR 5.50; 95% CI, 4.31- 7.02) and developmental language disorder (aHR 8.67; 95% CI, 7.27-10.33) at 4-6 years of age., Conclusion: Widespread nationwide implementation of screening programs before 24 months was effective in identifying NDDs at 4-6 years of age. Further strategies integrating with referral and intervention systems should be established., Impact: We investigated the screening effect of nationwide developmental screening program on neurodevelopmental disorders using nationwide data. Gross motor delay during infancy was significant predictor of later neurodevelopmental disorders. Language, cognitive, and social delay before 24 months of age was associated with later autism spectrum disorders and developmental language disorders. Widespread nationwide implementation of screening programs before 24 months was effective in identifying NDDs at 4-6 years of age and should be encouraged., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Traditional herbal medicine, rooted in a long history of use in East Asia, combines several herbs to create treatments showing high efficacy with minimal side effects, for specific diseases. Such combination therapies represent a potential reservoir of new drugs for treating multifactorial and incurable chronic diseases. However, the complexity of their mechanisms of action due to the combination of multiple compounds, has limited their research integration into modern pharmacological science. To address this challenge, we constructed drug-induced transcriptome data for herbal medicines through systematic experiments, analyzed with the aid of various omics databases. We introduce KORE-Map 1.0 (Korean medicine Omics Resource Extension Map), the first comprehensive resource of drug-derived transcriptome data for representative tonifying herbal medicines, effective in enhancing the immune system. This dataset aims to provide novel insights into the combinatorial mechanisms of these herbal medicines and to aid in the discovery of new therapeutic targets and indications for various incurable diseases., (© 2024. The Author(s).)

Network analysis has become a crucial tool in genetic research, enabling the exploration of associations between genes and diseases. Its utility extends beyond genetics to include the assessment of environmental factors. Unipartite network analysis is commonly used in genomics to visualize initial insights and relationships among variables. Syndromic diseases, such as metabolic syndrome, are characterized by the simultaneous occurrence of various signs, symptoms, and clinicopathological features. Metabolic syndrome encompasses hypertension, diabetes, obesity, and dyslipidemia, and both genetic and environmental factors contribute to its development. Given that relevant data often consist of distinct sets of variables, a more intuitive visualization method is needed. This study applied multipartite network analysis as an effective method to understand the associations among genetic, environmental, and disease components in syndromic diseases. We considered three distinct variable sets: genetic factors, environmental factors, and disease components. The process involved projecting a tripartite network onto a two-mode bipartite network and then simplifying it into a one-mode network. This approach facilitated the visualization of relationships among factors across different sets and within individual sets. To transition from multipartite to unipartite networks, we suggest both sequential and concurrent projection methods. Data from the Korean Association Resource (KARE) project were utilized, including 352,228 SNPs from 8840 individuals, alongside information on environmental factors such as lifestyle, dietary, and socioeconomic factors. The single-SNP analysis step filtered SNPs, supplemented by reference SNPs reported in a genome-wide association study catalog. The resulting network patterns differed significantly by sex: demographic factors and fat intake were crucial for women, while alcohol consumption was central for men. Indirect relationships were identified through projected bipartite networks, revealing that SNPs such as rs4244457, rs2156552, and rs10899345 had lifestyle interactions on metabolic components. Our approach offers several advantages: it simplifies the visualization of complex relationships among different datasets, identifies environmental interactions, and provides insights into SNP clusters sharing common environmental factors and metabolic components. This framework provides a comprehensive approach to elucidate the mechanisms underlying complex diseases like metabolic syndrome., (© 2024. The Author(s).)

Metabolic syndrome (MetS) is a complex disorder characterized by a cluster of metabolic abnormalities, including abdominal obesity, hypertension, elevated triglycerides, reduced high-density lipoprotein cholesterol, and impaired glucose tolerance. It poses a significant public health concern, as individuals with MetS are at an increased risk of developing cardiovascular diseases and type 2 diabetes. Early and accurate identification of individuals at risk for MetS is essential. Various machine learning approaches have been employed to predict MetS, such as logistic regression, support vector machines, and several boosting techniques. However, these methods use MetS as a binary status and do not consider that MetS comprises five components. Therefore, a method that focuses on these characteristics of MetS is needed. In this study, we propose a multi-task deep learning model designed to predict MetS and its five components simultaneously. The benefit of multi-task learning is that it can manage multiple tasks with a single model, and learning related tasks may enhance the model's predictive performance. To assess the efficacy of our proposed method, we compared its performance with that of several single-task approaches, including logistic regression, support vector machine, CatBoost, LightGBM, XGBoost and one-dimensional convolutional neural network. For the construction of our multi-task deep learning model, we utilized data from the Korean Association Resource (KARE) project, which includes 352,228 single nucleotide polymorphisms (SNPs) from 7729 individuals. We also considered lifestyle, dietary, and socio-economic factors that affect chronic diseases, in addition to genomic data. By evaluating metrics such as accuracy, precision, F1-score, and the area under the receiver operating characteristic curve, we demonstrate that our multi-task learning model surpasses traditional single-task machine learning models in predicting MetS., (© 2024. The Author(s).)

Parkinson's disease (PD) is a common neurodegenerative disorder with a significant risk proportion driven by genetics. While much progress has been made, most of the heritability remains unknown. This is in-part because previous genetic studies have focused on the contribution of single nucleotide variants. More complex forms of variation, such as structural variants and tandem repeats, are already associated with several synucleinopathies. However, because more sophisticated sequencing methods are usually required to detect these regions, little is understood regarding their contribution to PD. One example is a polymorphic CT-rich region in intron 4 of the SNCA gene. This haplotype has been suggested to be associated with risk of Lewy Body (LB) pathology in Alzheimer's Disease and SNCA gene expression, but is yet to be investigated in PD. Here, we attempt to resolve this CT-rich haplotype and investigate its role in PD. We performed targeted PacBio HiFi sequencing of the region in 1375 PD cases and 959 controls. We replicate the previously reported associations and a novel association between two PD risk SNVs (rs356182 and rs5019538) and haplotype 4, the largest haplotype. Through quantitative trait locus analyzes we identify a significant haplotype 4 association with alternative CAGE transcriptional start site usage, not leading to significant differential SNCA gene expression in post-mortem frontal cortex brain tissue. Therefore, disease association in this locus might not be biologically driven by this CT-rich repeat region. Our data demonstrates the complexity of this SNCA region and highlights that further follow up functional studies are warranted., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Ischemic colitis (IC) and sarcopenia are associated with aging and multiple comorbidities. We aimed to investigate the prevalence and predictive role of sarcopenia in patients with IC. We retrospectively analyzed 225 hospitalized patients (median age, 72 years; women, 67.1%; severe IC, 34.2%) who were diagnosed with IC between January 2007 and February 2022. Sarcopenia was defined as the skeletal muscle index at the third lumbar vertebra determined by computed tomography. It was present in 49.3% (n = 111) of the patients and was significantly associated with severe IC compared to those without sarcopenia (48.6% vs. 20.2%, P < 0.001). Sarcopenia was associated with extended hospitalization (median: 8 vs. 6 days, P < 0.001) and fasting periods (4 vs. 3 days, P = 0.004), as well as prolonged antibiotic use (9 vs. 7 days, P = 0.039). Sarcopenia was linked to a higher risk of surgery or mortality (9.0% vs. 0%, P = 0.001) and independently predicted this outcome (odds ratio [OR], 11.17; 95% confidence interval [CI], 1.24‒1467.65, P = 0.027). It was prevalent among hospitalized patients with IC, potentially indicating severe IC and a worse prognosis. This underscores the importance of meticulous monitoring, immediate medical intervention, and timely surgical consideration., (© 2024. The Author(s).)

Large-scale outflows driven by supermassive black holes are thought to have a fundamental role in suppressing star formation in massive galaxies. However, direct observational evidence for this hypothesis is still lacking, particularly in the young universe where star-formation quenching is remarkably rapid 1-3 , thus requiring effective removal of gas 4 as opposed to slow gas heating 5,6 . Although outflows of ionized gas are frequently detected in massive distant galaxies 7 , the amount of ejected mass is too small to be able to suppress star formation 8,9 . Gas ejection is expected to be more efficient in the neutral and molecular phases 10 , but at high redshift these have only been observed in starbursts and quasars 11,12 . Here we report JWST spectroscopy of a massive galaxy experiencing rapid quenching at a redshift of 2.445. We detect a weak outflow of ionized gas and a powerful outflow of neutral gas, with a mass outflow rate that is sufficient to quench the star formation. Neither X-ray nor radio activity is detected; however, the presence of a supermassive black hole is suggested by the properties of the ionized gas emission lines. We thus conclude that supermassive black holes are able to rapidly suppress star formation in massive galaxies by efficiently ejecting neutral gas., (© 2024. The Author(s).)

Although sevoflurane is generally considered safe, reports suggest that sevoflurane may cause postoperative liver injury more frequently than previously believed. Therefore, we aimed to compare the incidence of clinically significant postoperative liver injury following non-cardiac surgery between patients who underwent sevoflurane anesthesia and propofol-based total intravenous anesthesia. We retrospectively reviewed adult surgical patients from January 2010 to September 2022 who underwent general anesthesia in our center using sevoflurane or propofol over 3 h. After 1:1 propensity score matching, the incidence of postoperative liver injury was compared between the two groups. Out of 58,300 patients reviewed, 44,345 patients were included in the analysis. After propensity score matching, 7767 patients were included in each group. The incidence of postoperative liver injury was 1.4% in the sevoflurane group, which was similar to that in the propofol group (1.6%; p = 0.432). Comparison of the severity of postoperative alanine aminotransferase elevation showed that the incidence of borderline and mild elevation was higher in the sevoflurane group, but there was no difference in the incidence of moderate and severe elevation. In conclusion, sevoflurane anesthesia over 3 h was not associated with a higher incidence of clinically significant postoperative liver injury compared to propofol anesthesia., (© 2024. The Author(s).)

Tumor-associated macrophages (TAMs) are vital contributors to the growth, metastasis, and therapeutic resistance of various cancers, including hepatocellular carcinoma (HCC). However, the exact phenotype of TAMs and the mechanisms underlying their modulation for therapeutic purposes have not been determined. Here, we present compelling evidence that glutamine-derived aspartate in TAMs stimulates spermidine production through the polyamine synthesis pathway, thereby increasing the translation efficiency of HIF-1α via eIF5A hypusination. Consequently, augmented translation of HIF-1α drives TAMs to undergo an increase glycolysis and acquire a metabolic phenotype distinct from that of M2 macrophages. Finally, eIF5A levels in tumor stromal lesions were greater than those in nontumor stromal lesions. Additionally, a higher degree of tumor stromal eIF5A hypusination was significantly associated with a more advanced tumor stage. Taken together, these data highlight the potential of inhibiting hypusinated eIF5A by targeting glutamine metabolism in TAMs, thereby opening a promising avenue for the development of novel therapeutic approaches for HCC., (© 2024. The Author(s).)

Recent studies have demonstrated that the three-dimensional conformation of the chromatin plays a crucial role in gene regulation, with aberrations potentially leading to various diseases. Advanced methodologies have revealed a link between the chromatin conformation and biological function. This review divides these methodologies into sequencing-based and imaging-based methodologies, tracing their development over time. We particularly highlight innovative techniques that facilitate the simultaneous mapping of RNAs, histone modifications, and proteins within the context of the 3D architecture of chromatin. This multimodal integration substantially improves our ability to establish a robust connection between the spatial arrangement of molecular components in the nucleus and their functional roles. Achieving a comprehensive understanding of gene regulation requires capturing diverse data modalities within individual cells, enabling the direct inference of functional relationships between these components. In this context, imaging-based technologies have emerged as an especially promising approach for gathering spatial information across multiple components in the same cell., (© 2024. The Author(s).)

Intravesical treatment using either reovirus or natural killer (NK) cells serves as an efficient strategy for the treatment of bladder cancer cells (BCCs); however, corresponding monotherapies have often shown modest cytotoxicity. The potential of a locoregional combination using high-dose reovirus and NK cell therapy in an intravesical approach has not yet been studied. In this study, we evaluated the effectiveness of reoviruses and expanded NK cells (eNK) as potential strategies for the treatment of bladder cancer. The anti-tumor effects of mono-treatment with reovirus type 3 Dearing strain (RC402 and RP116) and in combination with interleukin (IL)-18/-21-pretreated eNK cells were investigated on BCC lines (5637, HT-1376, and 253J-BV) using intravesical therapy to simulate in vitro model. RP116 and IL-18/-21-pretreated eNK cells exhibited effective cytotoxicity against grade 1 carcinoma (5637 cells) when used alone, but not against HT-1376 (grade 2 carcinoma) and 253J-BV cells (derived from a metastatic site). Notably, combining RP116 with IL-18/-21-pretreated eNK cells displayed effective cytotoxicity against both HT-1376 and 253J-BV cells. Our findings underscore the potential of a combination therapy using reoviruses and NK cells as a promising strategy for treating bladder cancer., (© 2024. The Author(s).)

Particulate matter (PM) is a global environmental hazard, which affects human health through free radical production, cell death induction, and immune responses. PM activates inflammasomes leading to excessive inflammatory responses and induces ferroptosis, a type of cell death. Despite ongoing research on the correlation among PM-induced ferroptosis, immune response, and inflammasomes, the underlying mechanism of this relationship has not been elucidated. In this study, we demonstrated the levels of PM-induced cell death and immune responses in murine macrophages, J774A.1 and RAW264.7, depending on the size and composition of particulate matter. PM 2.5 , with extraction ions, induced significant levels of cell death and immune responses; it induces lipid peroxidation, iron accumulation, and reactive oxygen species (ROS) production, which characterize ferroptosis. In addition, inflammasome-mediated cell death occurred owing to the excessive activation of inflammatory responses. PM-induced iron accumulation activates ferroptosis and inflammasome formation through ROS production; similar results were observed in vivo. These results suggest that the link between ferroptosis and inflammasome formation induced by PM, especially PM 2.5 with extraction ions, is established through the iron-ROS axis. Moreover, this study can effectively facilitate the development of a new therapeutic strategy for PM-induced immune and respiratory diseases., (© 2024. The Author(s).)

Scoliosis is a three-dimensional spinal deformity, and paraspinal muscles play an important role as stabilizers of the spinal curve. In this prospective study, we compared elasticity changes in the paraspinal muscles of adolescent patients with scoliosis after surgery or bracing. Elasticity was measured on the concave and convex sides of the paraspinal muscles at the apex of the curve at the beginning of treatment and 6 and 12 months after treatment. Twenty-six patients with correction surgery (n = 15) or bracing (n = 11) were included. At initial evaluation, the Cobb angle was larger in the surgery group (72.3 ± 20.2° in surgery vs. 30.6 ± 5.1° in brace, p < 0.001). The estimated mean elasticity value of the paraspinal muscles was lower in the surgery group at baseline on the convex side (15.8 vs. 22.8 kPa, p = 0.037) and 6 months on both the concave (12.1 vs. 22.7 kPa, p = 0.004) and convex (13.4 vs. 23.8 kPa, p = 0.005) sides. There was a significant stiffness decrease from baseline to 6 months on the concave side in the surgery group (5.9 kPa, p = 0.025). However, the elasticity change recovered at 12 months without significant differences between the two groups., (© 2024. The Author(s).)

Glioblastoma multiforme (GBM) is the most fatal form of brain cancer in humans, with a dismal prognosis and a median overall survival rate of less than 15 months upon diagnosis. Glioma stem cells (GSCs), have recently been identified as key contributors in both tumor initiation and therapeutic resistance in GBM. Both public dataset analysis and direct differentiation experiments on GSCs have demonstrated that CREB5 is more highly expressed in undifferentiated GSCs than in differentiated GSCs. Additionally, gene silencing by short hairpin RNA (shRNA) of CREB5 has prevented the proliferation and self-renewal ability of GSCs in vitro and decreased their tumor forming ability in vivo. Meanwhile, RNA-sequencing, luciferase reporter assay, and ChIP assay have all demonstrated the closely association between CREB5 and OLIG2. These findings suggest that targeting CREB5 could be an effective approach to overcoming GSCs., (© 2024. The Author(s).)

Air pollution is an environmental risk factor linked to multiple human diseases including cardiovascular diseases (CVDs). While particulate matter (PM) emitted by diesel exhaust damages multiple organ systems, heart disease is one of the most severe pathologies affected by PM. However, the in vivo effects of diesel exhaust particles (DEP) on the heart and the molecular mechanisms of DEP-induced heart dysfunction have not been investigated. In the current study, we attempted to identify the proteomic signatures of heart fibrosis caused by diesel exhaust particles (DEP) in CVDs-prone apolipoprotein E knockout (ApoE -/- ) mice model using tandem mass tag (TMT)-based quantitative proteomic analysis. DEP exposure induced mild heart fibrosis in ApoE -/- mice compared with severe heart fibrosis in ApoE -/- mice that were treated with CVDs-inducing peptide, angiotensin II. TMT-based quantitative proteomic analysis of heart tissues between PBS- and DEP-treated ApoE -/- mice revealed significant upregulation of proteins associated with platelet activation and TGFβ-dependent pathways. Our data suggest that DEP exposure could induce heart fibrosis, potentially via platelet-related pathways and TGFβ induction, causing cardiac fibrosis and dysfunction., (© 2023. The Author(s).)

During the COVID-19 pandemic, the world population faced various mental health challenges, highlighting a need for new community-based psychosocial interventions. This study aimed to investigate the effectiveness and feasibility of Nature-Based Therapy (NBT) for the community experiencing psychological distress during the pandemic. A multi-site trial comparing NBT and control groups was conducted in Korea with 291 participants exhibiting mild to severe depression or anxiety. A total of 192 participated in 30 sessions of therapeutic gardening, while 99 remained in the control group. Psychological distress and well-being were assessed using seven measures of depression, anxiety, daily activity, life satisfaction, mindfulness, stress, and loneliness. The effect sizes (Cohen's d) of NBT compared to the control group were medium to large: depression (0.583), anxiety (0.728), daily activity (1.002), life satisfaction (0.786), mindfulness (0.645), stress (0.903), and loneliness (0.695). Multilevel analysis revealed significant Time × Group interaction effects for all measures. Pearson correlation (r = - 0.28 to 0.71) showed that changes in all variables correlated significantly with each other, with small to large effect sizes. Therapeutic alliance at post-test positively moderated the intervention effects on the outcomes. We concluded that NBT is a promising psychosocial intervention for treating psychological distress for community dwellers., (© 2023. The Author(s).)

Forests are a substantial terrestrial carbon sink, but anthropogenic changes in land use and climate have considerably reduced the scale of this system 1 . Remote-sensing estimates to quantify carbon losses from global forests 2-5 are characterized by considerable uncertainty and we lack a comprehensive ground-sourced evaluation to benchmark these estimates. Here we combine several ground-sourced 6 and satellite-derived approaches 2,7,8 to evaluate the scale of the global forest carbon potential outside agricultural and urban lands. Despite regional variation, the predictions demonstrated remarkable consistency at a global scale, with only a 12% difference between the ground-sourced and satellite-derived estimates. At present, global forest carbon storage is markedly under the natural potential, with a total deficit of 226 Gt (model range = 151-363 Gt) in areas with low human footprint. Most (61%, 139 Gt C) of this potential is in areas with existing forests, in which ecosystem protection can allow forests to recover to maturity. The remaining 39% (87 Gt C) of potential lies in regions in which forests have been removed or fragmented. Although forests cannot be a substitute for emissions reductions, our results support the idea 2,3,9 that the conservation, restoration and sustainable management of diverse forests offer valuable contributions to meeting global climate and biodiversity targets., (© 2023. The Author(s).)

Birefringence, an inherent characteristic of optically anisotropic materials, is widely utilized in various imaging applications ranging from material characterizations to clinical diagnosis. Polarized light microscopy enables high-resolution, high-contrast imaging of optically anisotropic specimens, but it is associated with mechanical rotations of polarizer/analyzer and relatively complex optical designs. Here, we present a form of lens-less polarization-sensitive microscopy capable of complex and birefringence imaging of transparent objects without an optical lens and any moving parts. Our method exploits an optical mask-modulated polarization image sensor and single-input-state LED illumination design to obtain complex and birefringence images of the object via ptychographic phase retrieval. Using a camera with a pixel size of 3.45 μm, the method achieves birefringence imaging with a half-pitch resolution of 2.46 μm over a 59.74 mm 2  field-of-view, which corresponds to a space-bandwidth product of 9.9 megapixels. We demonstrate the high-resolution, large-area, phase and birefringence imaging capability of our method by presenting the phase and birefringence images of various anisotropic objects, including a monosodium urate crystal, and excised mouse eye and heart tissues., (© 2023. The Author(s).)

EWS RNA binding protein 1 (EWSR1) is a multifunctional protein whose epigenetic signatures contribute to the pathogenesis of various human diseases, such as neurodegenerative disorders, skin development, and tumorigenic processes. However, the specific cellular functions and physiological characteristics of EWSR1 remain unclear. In this study, we used quantitative mass spectrometry-based proteomics with tandem mass tag labeling to investigate the global proteome changes in brain tissue in Ewsr1 knockout and wild-type mice. From 9115 identified proteins, we selected 118 differentially expressed proteins, which is common to three quantitative data processing strategies including only protein level normalizations and spectrum-protein level normalization. Bioinformatics analysis of these common differentially expressed proteins revealed that proteins up-regulated in Ewsr1 knockout mouse are mostly related to the positive regulation of bone remodeling and inflammatory response. The down-regulated proteins were associated with the regulation of neurotransmitter levels or amino acid metabolic processes. Collectively, these findings provide insight into the physiological function and pathogenesis of EWSR1 on protein level. Better understanding of EWSR1 and its protein interactions will advance the field of clinical research into neuronal disorders. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD026994., (© 2023. Springer Nature Limited.)

Determining the drivers of non-native plant invasions is critical for managing native ecosystems and limiting the spread of invasive species 1,2 . Tree invasions in particular have been relatively overlooked, even though they have the potential to transform ecosystems and economies 3,4 . Here, leveraging global tree databases 5-7 , we explore how the phylogenetic and functional diversity of native tree communities, human pressure and the environment influence the establishment of non-native tree species and the subsequent invasion severity. We find that anthropogenic factors are key to predicting whether a location is invaded, but that invasion severity is underpinned by native diversity, with higher diversity predicting lower invasion severity. Temperature and precipitation emerge as strong predictors of invasion strategy, with non-native species invading successfully when they are similar to the native community in cold or dry extremes. Yet, despite the influence of these ecological forces in determining invasion strategy, we find evidence that these patterns can be obscured by human activity, with lower ecological signal in areas with higher proximity to shipping ports. Our global perspective of non-native tree invasion highlights that human drivers influence non-native tree presence, and that native phylogenetic and functional diversity have a critical role in the establishment and spread of subsequent invasions., (© 2023. The Author(s).)

The emergence of large language models has led to the development of powerful tools such as ChatGPT that can produce text indistinguishable from human-generated work. With the increasing accessibility of such technology, students across the globe may utilize it to help with their school work-a possibility that has sparked ample discussion on the integrity of student evaluation processes in the age of artificial intelligence (AI). To date, it is unclear how such tools perform compared to students on university-level courses across various disciplines. Further, students' perspectives regarding the use of such tools in school work, and educators' perspectives on treating their use as plagiarism, remain unknown. Here, we compare the performance of the state-of-the-art tool, ChatGPT, against that of students on 32 university-level courses. We also assess the degree to which its use can be detected by two classifiers designed specifically for this purpose. Additionally, we conduct a global survey across five countries, as well as a more in-depth survey at the authors' institution, to discern students' and educators' perceptions of ChatGPT's use in school work. We find that ChatGPT's performance is comparable, if not superior, to that of students in a multitude of courses. Moreover, current AI-text classifiers cannot reliably detect ChatGPT's use in school work, due to both their propensity to classify human-written answers as AI-generated, as well as the relative ease with which AI-generated text can be edited to evade detection. Finally, there seems to be an emerging consensus among students to use the tool, and among educators to treat its use as plagiarism. Our findings offer insights that could guide policy discussions addressing the integration of artificial intelligence into educational frameworks., (© 2023. The Author(s).)

Cancer pain is a challenging clinical problem that is encountered in the management of cancer pain. We aimed to investigate the clinical relevance of deep learning models that predict the onset of cancer pain exacerbation in hospitalized patients. We defined cancer pain exacerbation (CPE) as the pain with a numerical rating scale (NRS) score of ≥ 4. We investigated the performance of the deep learning models using the Matthews correlation coefficient (MCC) with different input lengths and time binning. All the pain records were obtained from the electronic medical records of the hematology-oncology wards in a Samsung Medical Center between July 2016 and February 2020. The model was externally validated using the holdout method with 20% of the datasets. The most common type of cancer was lung cancer (n = 745, 21.7%), and the median CPE per day was 1.01. The NRS pain records showed circadian patterns that correlated with NRS pain patterns of the previous days. The correlation of the NRS scores showed a positive association with the closeness of the NRS pattern of the day with forecast date and size of time binning. The long short-term memory-based model exhibited a good performance by demonstrating 9 times the best performance and 8 times the second-best performance among 21 different settings. The best performance was achieved with 120 h input and 12 h bin lengths (MCC: 0.4927). Our study demonstrated the possibility of predicting CPE using deep learning models, thereby suggesting that preemptive cancer pain management using deep learning could potentially improve patients' daily life., (© 2023. The Author(s).)

Chatbots have become an increasingly popular tool in the field of health services and communications. Despite chatbots' significance amid the COVID-19 pandemic, few studies have performed a rigorous evaluation of the effectiveness of chatbots in improving vaccine confidence and acceptance. In Thailand, Hong Kong, and Singapore, from February 11th to June 30th, 2022, we conducted multisite randomised controlled trials (RCT) on 2,045 adult guardians of children and seniors who were unvaccinated or had delayed vaccinations. After a week of using COVID-19 vaccine chatbots, the differences in vaccine confidence and acceptance were compared between the intervention and control groups. Compared to non-users, fewer chatbot users reported decreased confidence in vaccine effectiveness in the Thailand child group [Intervention: 4.3 % vs. Control: 17%, P = 0.023]. However, more chatbot users reported decreased vaccine acceptance [26% vs. 12%, P = 0.028] in Hong Kong child group and decreased vaccine confidence in safety [29% vs. 10%, P = 0.041] in Singapore child group. There was no statistically significant change in vaccine confidence or acceptance in the Hong Kong senior group. Employing the RE-AIM framework, process evaluation indicated strong acceptance and implementation support for vaccine chatbots from stakeholders, with high levels of sustainability and scalability. This multisite, parallel RCT study on vaccine chatbots found mixed success in improving vaccine confidence and acceptance among unvaccinated Asian subpopulations. Further studies that link chatbot usage and real-world vaccine uptake are needed to augment evidence for employing vaccine chatbots to advance vaccine confidence and acceptance., (© 2023. The Author(s).)

The proliferation and migration of vascular smooth muscle cells (VSMCs) after vascular injury lead to neointimal hyperplasia, thus aggravating vascular diseases. However, the molecular mechanisms underlying neointima formation are not fully elucidated. Extracellular vesicles (EVs) are mediators of various intercellular communications. The potential of EVs as regulators in cardiovascular diseases has raised significant interest. In the current study we investigated the role of circulating small extracellular vesicles (csEVs), the most abundant EVs (10 10 EVs/mL serum) in VSMC functions. csEVs were prepared from bovine, porcine or rat serum. We showed that incubation with csEVs (0.5 × 10 10 -2 × 10 10 ) dose-dependently enhanced the proliferation and migration of VSMCs via the membrane phosphatidylserine (PS). In rats with ligation of right carotid artery, we demonstrated that application of csEVs in the ligated vessels aggravated neointima formation via interaction of membrane PS with injury. Furthermore, incubation with csEVs markedly enhanced the phosphorylation of AXL and MerTK in VSMCs. Pretreatment with BSM777607 (pan-TAM inhibitor), bemcentinib (AXL inhibitor) or UNC2250 (MerTK inhibitor) blocked csEV-induced proliferation and migration of VSMCs. We revealed that csEV-activated AXL and MerTK shared the downstream signaling pathways of Akt, extracellular signal-regulated kinase (ERK) and focal adhesion kinase (FAK) that mediated the effects of csEVs. We also found that csEVs increased the expression of AXL through activation of transcription factor YAP, which might constitute an AXL-positive feedback loop to amplify the signals. Finally, we demonstrated that dual inhibition of AXL/MerTK by ONO-7475 (0.1 µM) effectively hindered csEV-mediated proliferation and migration of VSMCs in ex vivo mouse aorta injury model. Based on these results, we propose an essential role for csEVs in proliferation and migration of VSMCs and highlight the feasibility of dual AXL/MerTK inhibitors in the treatment of vascular diseases., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Acyl myricetins (monopropionyl-, dipropionyl-, and monooctanoyl-myricetin, termed as MP 1 , MP 2 , and MO 1 , respectively) were synthesized through enzymatic or non-enzymatic esterification reaction of myricetin aglycone. Structure study indicated the hydroxyl group at C4' in B-ring was highly susceptible to acylation. Over its parental myricetin, acylated compounds showed enhanced lipophilicity (from 7.4- to 26.3-fold) and oxidative stability (from 1.9- to 3.1-fold) on the basis of logP and decay rate, respectively. MO 1 , presenting the physicochemical superiority compared to the others, provided lowest EC 50 value of 2.51 μM on inhibition of neutrotransmitter release and CC 50 value of 59.0 μM, leading to widest therapeutic window. All myricetin esters did not show any irritation toxicity when assessed with a chicken embryo assay. This study describes information on acylation of myricetin that has not yet been explored, and suggests that MO 1 has membrane fusion-arresting and anti-neuroexocytotic potential for industrial application due to its enhanced biological properties., (© 2023. The Author(s).)

Laser-Induced Breakdown Spectroscopy (LIBS) is a promising technology for in-situ analysis of Plasma-Facing Components in magnetic confinement fusion facilities. It is of major interest to monitor the hydrogen isotope retention i.e. tritium and deuterium over many operation hours to guarantee safety and availability of the future reactor. In our studies we use ultraviolet femtosecond laser pulses to analyze tungsten (W) tiles that were exposed to a deuterium plasma in the linear plasma device PSI-2, which mimics conditions at the first wall. A high-resolution spectrometer is used to detect the Balmer-[Formula: see text] transition of the surface from implanted hydrogen isotopes (H and D). We use Calibration Free CF-LIBS to quantify the amount of deuterium stored in W. This proof-of-principle study shows the applicability of femtosecond lasers for the detection of low deuterium concentration as present in first wall material of prevailing fusion experiments., (© 2023. The Author(s).)

Single-cell technologies have enabled the characterization of the tumour microenvironment at unprecedented depth and have revealed vast cellular diversity among tumour cells and their niche. Anti-tumour immunity relies on cell-cell relationships within the tumour microenvironment 1,2 , yet many single-cell studies lack spatial context and rely on dissociated tissues 3 . Here we applied imaging mass cytometry to characterize the immunological landscape of 139 high-grade glioma and 46 brain metastasis tumours from patients. Single-cell analysis of more than 1.1 million cells across 389 high-dimensional histopathology images enabled the spatial resolution of immune lineages and activation states, revealing differences in immune landscapes between primary tumours and brain metastases from diverse solid cancers. These analyses revealed cellular neighbourhoods associated with survival in patients with glioblastoma, which we leveraged to identify a unique population of myeloperoxidase (MPO)-positive macrophages associated with long-term survival. Our findings provide insight into the biology of primary and metastatic brain tumours, reinforcing the value of integrating spatial resolution to single-cell datasets to dissect the microenvironmental contexture of cancer., (© 2023. The Author(s).)

Theories of scientific and technological change view discovery and invention as endogenous processes 1,2 , wherein previous accumulated knowledge enables future progress by allowing researchers to, in Newton's words, 'stand on the shoulders of giants' 3-7 . Recent decades have witnessed exponential growth in the volume of new scientific and technological knowledge, thereby creating conditions that should be ripe for major advances 8,9 . Yet contrary to this view, studies suggest that progress is slowing in several major fields 10,11 . Here, we analyse these claims at scale across six decades, using data on 45 million papers and 3.9 million patents from six large-scale datasets, together with a new quantitative metric-the CD index 12 -that characterizes how papers and patents change networks of citations in science and technology. We find that papers and patents are increasingly less likely to break with the past in ways that push science and technology in new directions. This pattern holds universally across fields and is robust across multiple different citation- and text-based metrics 1,13-17 . Subsequently, we link this decline in disruptiveness to a narrowing in the use of previous knowledge, allowing us to reconcile the patterns we observe with the 'shoulders of giants' view. We find that the observed declines are unlikely to be driven by changes in the quality of published science, citation practices or field-specific factors. Overall, our results suggest that slowing rates of disruption may reflect a fundamental shift in the nature of science and technology., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Circadian rhythms regulate diverse aspects of gastrointestinal physiology ranging from the composition of microbiota to motility. However, development of the intestinal circadian clock and detailed mechanisms regulating circadian physiology of the intestine remain largely unknown. In this report, we show that both pluripotent stem cell-derived human intestinal organoids engrafted into mice and patient-derived human intestinal enteroids possess circadian rhythms and demonstrate circadian phase-dependent necrotic cell death responses to Clostridium difficile toxin B (TcdB). Intriguingly, mouse and human enteroids demonstrate anti-phasic necrotic cell death responses to TcdB. RNA-Seq analysis shows that ~3-10% of the detectable transcripts are rhythmically expressed in mouse and human enteroids. Remarkably, we observe anti-phasic gene expression of Rac1, a small GTPase directly inactivated by TcdB, between mouse and human enteroids, and disruption of Rac1 abolishes clock-dependent necrotic cell death responses. Our findings uncover robust functions of circadian rhythms regulating clock-controlled genes in both mouse and human enteroids governing organism-specific, circadian phase-dependent necrotic cell death responses, and lay a foundation for human organ- and disease-specific investigation of clock functions using human organoids for translational applications., (© 2021 The Authors Published under the terms of the CC BY NC ND 4.0 license.)

Posttransplantation diabetes mellitus (PTDM) is an important metabolic complication after KT that causes graft failure and cardiovascular complications in kidney transplantation (KT) recipients. Using the national claim data of South Korea, 7612 KT recipients between 2009 and 2017 were analyzed. PTDM was defined as a consecutive 30-day prescription history of antidiabetic medication after KT. Among these patients, 24.7% were diagnosed with PTDM, and 51.9% were diagnosed within 6 months after KT. Compared to patients without PTDM, those with PTDM were older, more likely to be men, more likely to be diagnosed with hypertension and cardio-cerebrovascular disease, and experienced more rejection episodes requiring high-dose steroid treatment after KT. During the follow-up, 607 DCGFs, 230 DWGFs, 244 MACEs, and 260 all-cause mortality events occurred. Patients with PTDM showed a higher risk of DCGF (adjusted hazard ratio [aHR] 1.49; 95% confidence interval [CI] 1.22-1.82; P < 0.001) and MACEs (aHR 1.76; 95% CI 1.33-2.31; P < 0.001) than patients without PTDM. The risks for all clinical outcomes were higher in the insulin group than in the non-use insulin group. PTDM in KT recipients resulted in both worse allograft and patient outcomes represented by DCGF and MACE, especially in patients needing insulin treatment., (© 2022. The Author(s).)

The role of serum lipids in Parkinson's disease (PD) remains controversial. We aimed to evaluate the association between time-varying serum lipid levels and the risk of PD. This study included an assessment of the complete lipid profiles of 200,454 individuals from the 2002-2019 Korean National Health Insurance Health Screening Cohort. Time-dependent Cox proportional hazard regression models were used to evaluate the association between serum lipid levels over time and the risk of PD. Individuals in the lowest tertile of total cholesterol and low-density lipoprotein cholesterol had a 1.17 times [hazard ratio (HR) 1.17; 95% confidence interval (CI) 1.04-1.31] and 1.19 times (HR 1.19; 95% CI 1.06-1.34) higher risk of PD than those in middle tertile, respectively. Individuals in the highest high-density lipoprotein cholesterol tertile had a 0.89 times (HR 0.89; 95% CI 0.79-1.00) lower risk of PD than those in middle tertile, but the association was less robust in sensitivity analyses. Serum triglyceride levels were not related to the risk of PD. Our results suggest that the serum total and low-density lipoprotein cholesterol levels over time are inversely associated with the risk of PD. Further research is warranted to confirm these findings and reveal the underlying mechanisms., (© 2022. The Author(s).)

This study aimed to determine whether significant associations exist between multicultural families and adolescent smoking risks in South Korea. Data from the Korea Youth Risk Behavior Web-based survey from 2016 to 2020 were analyzed. Participants were classified into four family types (South Korean mother-foreign father, South Korean father-foreign mother, both foreign parents, and both South Korean parents) according to their parents' country of birth and smoking was assessed using a self-reported questionnaire. A logistic regression analysis was used to examine the significance of the associations. Overall, 194,259 participants (boys: 94,793, girls: 99,466) enrolled in this study. Adolescents whose parents were born overseas were more likely to smoke than native South Korean adolescents (boys: odds ratio [OR] = 2.61, confidence interval [CI] = 1.79-3.81, girls: OR 3.94, CI 2.42-6.43). When the mother's country of birth was a developing country, there was an increased likelihood of girls smoking, and there was an increased likelihood of smoking among boys when the mother's country of birth was North Korea. When both parents were born abroad, and the mother's country of birth was a developing country, the likelihood of smoking risks among their multicultural teenage children increased. Policies and interventions need to be established and implemented to lower the smoking rate among multicultural teenagers., (© 2022. The Author(s).)

Chordoma is a malignant bone neoplasm demonstrating notochordal differentiation and it frequently involves axial skeleton. Most of chordomas are conventional type with varying amount of myxoid stroma. Previously known prognostic factors for conventional chordoma are not specific for chordoma: old age, metastasis, tumor extent, and respectability. Here, we aimed to investigate the histologic, radiologic, and transcriptomic differences in conventional chordoma based on the stromal component. A total of 45 patients diagnosed with conventional chordoma were selected between May 2011 and March 2020 from a single institution. Electronic medical records, pathology slides, and pretreatment magnetic resonance imaging (MRI) scans were reviewed. Of the 45 patients, ten cases (4 stroma-rich and 6 stroma-poor tumor) were selected for RNA sequencing, and available cases in the remainder were used for measuring target gene mRNA expression with qPCR for validation. Differential gene expression and gene set analysis were performed. Based on histologic evaluation, there were 25 (55.6%) stroma-rich and 20 (44.4%) stroma-poor cases. No clinical differences were found between the two groups. Radiologically, stroma-rich chordomas showed significant signal enhancement on MRI (72.4% vs 27.6%, p = 0.002). Upregulated genes in stroma-rich chordomas were cartilage-, collagen/extracellular matrix-, and tumor metastasis/progression-associated genes. Contrarily, tumor suppressor genes were downregulated in stroma-rich chordomas. On survival analysis, Kaplan-Meier plot was separated that showed inferior outcome of stroma-rich group, although statistically insignificant. In conclusion, the abundant stromal component of conventional chordoma enhanced well on MRI and possibly contributed to the biological aggressiveness that supported by transcriptomic characteristics. Further extensive investigation regarding radiologic-pathologic-transcriptomic correlation in conventional chordoma in a larger cohort could verify additional clinical significance., (© 2022. The Author(s).)

Diesel exhaust particles (DEP) are risk factors for endothelial cells (ECs) dysfunction. However, the mechanism by which DEP induce ECs apoptosis remains unclear. Here, we investigated how DEP induce death of human umbilical vein ECs (HUVECs), with a focus on the autophagy-mediated apoptotic pathway. DEP induced dose-dependent HUVECs death and exposure to the IC 50 concentration of DEP (70 µg/ml) led to apoptosis. DEP phosphorylated Beclin-1 (Ser93) and increased protein levels of p62 and LC3BII and the number of LC3B puncta, indicating autophagy initiation. DEP increased expression of pro- and mature forms of cathepsin D, which increases lysosomal activity. However, DEP suppressed expression of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins (STX17, VAMP8, SNAP29, YKT6, and STX7) to inhibit autolysosome formation, resulting in accumulation of autophagosomes. LC3B, p62, and caspase-8 form a tertiary complex in accumulated autophagosomes, which is known to serve as a platform for caspase-8 activation. Indeed, DEP activates caspase-8 and pretreatment with a caspase-8 inhibitor suppressed DEP-induced apoptosis. Furthermore, depletion of p62 decreased caspase-8 and caspase-3 activation and inhibited the DEP-induced apoptosis. Taken together, these findings demonstrated that DEP induced HUVECs apoptosis by inhibiting autophagosome maturation and identified caspase-8 as a novel mediator of DEP-induced ECs apoptosis., (© 2022. The Author(s).)

Temperature and salinity often define the distributions of aquatic organisms. This is at least partially true for Delta Smelt, an imperiled species endemic to the upper San Francisco Estuary. While much is known about the tolerances and distribution of Delta Smelt in relation to these parameters, little is known regarding the temperature and salinity preferences of the species. Therefore, the temperature and salinity preferences of sub-adult Delta Smelt were investigated across a wide range of thermal (8-28 °C) and salinity (0-23 ppt) conditions. Replicates of ten fish were allowed to swim between two circular chambers with different temperature or salinity, and the distribution of fish between the chambers was recorded. We found that Delta Smelt showed no temperature preference below 15 °C, a modest aversion to the warmer tank from 15 to 28 °C, and a strong aversion to the warmer tank with elevated mortality at temperatures above 28 °C. Delta Smelt also preferred lower salinities, and this preference became more pronounced as salinity increased toward 23 ppt. These results indicate that Delta Smelt can tolerate high temperatures and salinities for a short time, and that their preferences for lower temperature and salinity strengthens as these variables increase., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)