Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition.

It is increasingly appreciated that oncogenic transformation alters cellular metabolism to facilitate cell proliferation, but less is known about the metabolic changes that promote cancer cell aggressiveness. Here, we analyzed metabolic gene expression in cancer cell lines and found that a set of high-grade carcinoma lines expressing mesenchymal markers share a unique 44 gene signature, designated the "mesenchymal metabolic signature" (MMS). A FACS-based shRNA screen identified several MMS genes as essential for the epithelial-mesenchymal transition (EMT), but not for cell proliferation. Dihydropyrimidine dehydrogenase (DPYD), a pyrimidine-degrading enzyme, was highly expressed upon EMT induction and was necessary for cells to acquire mesenchymal characteristics in vitro and for tumorigenic cells to extravasate into the mouse lung. This role of DPYD was mediated through its catalytic activity and enzymatic products, the dihydropyrimidines. Thus, we identify metabolic processes essential for the EMT, a program associated with the acquisition of metastatic and aggressive cancer cell traits.

Disruption of sugar nucleotide clearance is a therapeutic vulnerability of cancer cells.

Identifying metabolic steps that are specifically required for the survival of cancer cells but are dispensable in normal cells remains a challenge1. Here we report a therapeutic vulnerability in a sugar nucleotide biosynthetic pathway that can be exploited in cancer cells with only a limited impact on normal cells. A systematic examination of conditionally essential metabolic enzymes revealed that UXS1, a Golgi enzyme that converts one sugar nucleotide (UDP-glucuronic acid, UDPGA) to another (UDP-xylose), is essential only in cells that express high levels of the enzyme immediately upstream of it, UGDH. This conditional relationship exists because UXS1 is required to prevent excess accumulation of UDPGA, which is produced by UGDH. UXS1 not only clears away UDPGA but also limits its production through negative feedback on UGDH. Excess UDPGA disrupts Golgi morphology and function, which impedes the trafficking of surface receptors such as EGFR to the plasma membrane and diminishes the signalling capacity of cells. UGDH expression is elevated in several cancers, including lung adenocarcinoma, and is further enhanced during chemoresistant selection. As a result, these cancer cells are selectively dependent on UXS1 for UDPGA detoxification, revealing a potential weakness in tumours with high levels of UGDH.

Immune Activation Profiles Elicited by Distinct, Repeated TLR Agonist Infusions in Rhesus Macaques.

TLR agonists are a promising class of immune system stimulants investigated for immunomodulatory applications in cancer immunotherapy and viral diseases. In this study, we sought to characterize the safety and immune activation achieved by different TLR agonists in rhesus macaques (Macaca mulatta), a useful preclinical model of complex immune interactions. Macaques received one of three TLR agonists, followed by plasma cytokine, immune cell subset representation, and blood cell activation measurements. The TLR4 agonist LPS administered i.v. induced very transient immune activation, including TNF-α expression and monocyte activation. The TLR7/8 agonist 2BXy elicited more persistent cytokine expression, including type I IFN, IL-1RA, and the proinflammatory IL-6, along with T cell and monocyte activation. Delivery of 2BXy i.v. and i.m. achieved comparable immune activation, which increased with escalating dose. Finally, i.v. bacillus Calmette-Guérin (BCG) vaccination (which activates multiple TLRs, especially TLR2/4) elicited the most pronounced and persistent innate and adaptive immune response, including strong induction of IFN-γ, IL-6, and IL-1RA. Strikingly, monocyte, T cell, and NK cell expression of the proliferation marker Ki67 increased dramatically following BCG vaccination. This aligned with a large increase in total and BCG-specific cells measured in the lung. Principal component analysis of the combined cytokine expression and cellular activation responses separated animals by treatment group, indicating distinct immune activation profiles induced by each agent. In sum, we report safe, effective doses and routes of administration for three TLR agonists that exhibit discrete immunomodulatory properties in primates and may be leveraged in future immunotherapeutic strategies.

Bridging physiology and pathology in AD.

The APP-processing pathway is a pathological component of Alzheimer's disease (AD), but there is no consensus regarding the physiological functions of APP and its products. Two studies (Nikolaev et al., 2009; Lauren et al., 2009) link the physiological and pathological aspects of APP processing. They show that the APP products, N-APP and Abeta42, are ligands for death receptor 6 and cellular prion protein, respectively, which are important in nervous system development and synaptic suppression.

Deep learning-based natural language processing for detecting medical symptoms and histories in emergency patient triage.

OBJECTIVE: The manual recording of electronic health records (EHRs) by clinicians in the emergency department (ED) is time-consuming and challenging. In light of recent advancements in large language models (LLMs) such as GPT and BERT, this study aimed to design and validate LLMs for automatic clinical diagnoses. The models were designed to identify 12 medical symptoms and 2 patient histories from simulated clinician-patient conversations within 6 primary symptom scenarios in emergency triage rooms. MATERIALS AND METHOD: We developed classification models by fine-tuning BERT, a transformer-based pre-trained model. We subsequently analyzed these models using eXplainable artificial intelligence (XAI) and the Shapley additive explanation (SHAP) method. A Turing test was conducted to ascertain the reliability of the XAI results by comparing them to the outcomes of tasks performed and explained by medical workers. An emergency medicine specialist assessed the results of both XAI and the medical workers. RESULTS: We fine-tuned four pre-trained LLMs and compared their classification performance. The KLUE-RoBERTa-based model demonstrated the highest performance (F1-score: 0.965, AUROC: 0.893) on human-transcribed script data. The XAI results using SHAP showed an average Jaccard similarity of 0.722 when compared with explanations of medical workers for 15 samples. The Turing test results revealed a small 6% gap, with XAI and medical workers receiving the mean scores of 3.327 and 3.52, respectively. CONCLUSION: This paper highlights the potential of LLMs for automatic EHR recording in Korean EDs. The KLUE-RoBERTa-based model demonstrated superior classification performance. Furthermore, XAI using SHAP provided reliable explanations for model outputs. The reliability of these explanations was confirmed by a Turing test.

Issues, challenges, and future perspectives of genetic counseling in Republic of Korea: Perspectives of laboratory physicians based on a 2022 survey.

The field of genetic counseling (GC) in the Republic of Korea has evolved from a single medical doctor's clinic to a multidisciplinary service with medical geneticists and non-medical professionals working as a team. Here, we assessed the current status of GC in the Republic of Korea based on professional surveys from the perspective of laboratory physicians. An electronic survey was designed and conducted, with the respondents being 50 certified laboratory physicians who were members of the Korean Society for Genetic Diagnostics. Among the 50 respondents, 12 (24%) operated GC clinics. The number of sessions and cases of GC have been on the rise over the last few years, and counseling for cancer genetics was the most common request. Most respondents considered a good understanding of the genetic test and the ability to interpret the test results as strengths of laboratory physicians as medical geneticists, while the lack of clinical experience was a weakness. Education programs regarding laboratory physicians' needs should be provided for high-quality counseling. Lastly, improving the efficiency of GC by strengthening the workforce through a multidisciplinary team is necessary.

Coupling structural evolution and oxygen-redox electrochemistry in layered transition metal oxides.

Lattice oxygen redox offers an unexplored way to access superior electrochemical properties of transition metal oxides (TMOs) for rechargeable batteries. However, the reaction is often accompanied by unfavourable structural transformations and persistent electrochemical degradation, thereby precluding the practical application of this strategy. Here we explore the close interplay between the local structural change and oxygen electrochemistry during short- and long-term battery operation for layered TMOs. The substantially distinct evolution of the oxygen-redox activity and reversibility are demonstrated to stem from the different cation-migration mechanisms during the dynamic de/intercalation process. We show that the π stabilization on the oxygen oxidation initially aids in the reversibility of the oxygen redox and is predominant in the absence of cation migrations; however, the π-interacting oxygen is gradually replaced by σ-interacting oxygen that triggers the formation of O-O dimers and structural destabilization as cycling progresses. More importantly, it is revealed that the distinct cation-migration paths available in the layered TMOs govern the conversion kinetics from π to σ interactions. These findings constitute a step forward in unravelling the correlation between the local structural evolution and the reversibility of oxygen electrochemistry and provide guidance for further development of oxygen-redox layered electrode materials.

A phase 2 study of stereotactic body radiation therapy for squamous cell carcinoma of the head and neck (SHINE): a single arm clinical trial protocol.

BACKGROUND: Cancers of the head and neck region are often characterized by locally advanced, non-metastatic disease. Standard treatments for advanced cervico-facial cancers of the skin or primary head and neck squamous cell carcinoma (HNSCC) include combinations of surgery, radiation and chemotherapy, which are associated with high rates of acute toxicity and complications. Stereotactic body radiotherapy (SBRT) has been shown to be a promising modality of treatment for this patient population in retrospective studies; to our knowledge, there are no prospective clinical studies evaluating the safety and efficacy of SBRT in these patients. METHODS: This phase 2, single institution, single arm study aims to evaluate response rates to SBRT in older age patients with locally advanced HNSCC for whom primary surgery is not recommended or performed. The intervention is SBRT 45 Gy in 5 fractions given every 3-4 days. Toxicity, quality of life and patient outcomes will be recorded regularly up to 24 months after completion of SBRT. DISCUSSION: For this patient population, SBRT may offer a shorter and more effective treatment than the current standard of care palliative regimens. If the study demonstrates that SBRT is safe and effective, then this may lead to randomized studies comparing conventional radiotherapy to SBRT for selected head and neck cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04435938 .  Date registered: June 17, 2020.

C9orf72/ALFA-1 controls TFEB/HLH-30-dependent metabolism through dynamic regulation of Rag GTPases.

Nutrient utilization and energy metabolism are critical for the maintenance of cellular homeostasis. A mutation in the C9orf72 gene has been linked to the most common forms of neurodegenerative diseases that include amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we have identified an evolutionarily conserved function of C9orf72 in the regulation of the transcription factor EB (TFEB), a master regulator of autophagic and lysosomal genes that is negatively modulated by mTORC1. Loss of the C. elegans orthologue of C9orf72, ALFA-1, causes the nuclear translocation of HLH-30/TFEB, leading to activation of lipolysis and premature lethality during starvation-induced developmental arrest in C. elegans. A similar conserved pathway exists in human cells, in which C9orf72 regulates mTOR and TFEB signaling. C9orf72 interacts with and dynamically regulates the level of Rag GTPases, which are responsible for the recruitment of mTOR and TFEB on the lysosome upon amino acid signals. These results have revealed previously unknown functions of C9orf72 in nutrient sensing and metabolic pathways and suggest that dysregulation of C9orf72 functions could compromise cellular fitness under conditions of nutrient stress.

Age at menopause and risk of heart failure and atrial fibrillation: a nationwide cohort study.

AIMS: This study aimed to examine the association of premature menopause and age at menopause with the risk of heart failure (HF) and atrial fibrillation (AF). METHODS AND RESULTS: A total of 1 401 175 postmenopausal women, who had undergone health examination provided by the Korean National Health Insurance Service, were included, and their reproductive histories were collected. Multivariable Cox proportional hazard models were performed to determine the hazard ratios (HRs) and 95% confidence intervals (CIs) of incident HF and AF, according to the history of premature menopause and age at menopause. At a mean follow-up of 9.1 years, there were 42 699 (3.0%) and 44 834 (3.2%) new cases of HF and AF, respectively. Women with history of premature menopause had an increased risk of HF (HR: 1.33, 95% CI: 1.26-1.40) and AF (HR: 1.09, 95% CI: 1.02-1.16), compared to women without the history. Compared with women aged ≥50 years at menopause, those aged 45-49, 40-44, and <40 years at menopause showed a significantly increased trend in HRs for the incident risk of both HF and AF (P for trend <0.001). The robustness of the results of a series of sensitivity analyses further strengthens the main findings. CONCLUSION: Our findings suggest that postmenopausal women with a history of premature menopause or early menopausal age may have an increased risk of HF and AF. These reproductive factors need to be considered for preventing the future risk of HF and AF.

A Taxonomic Hierarchy of Blockchain Consensus Algorithms: An Evolutionary Phylogeny Approach.

Countless endeavors have been undertaken to address the Byzantine Generals Problem, a generalization of the Two Generals Problem. The emergence of proof of work (PoW) for Bitcoin has led to various consensus algorithms diverging, and comparable existing consensus algorithms are being gradually utilized interchangeably, or only developed for each specific application domain. Our approach employs an evolutionary phylogeny method to classify blockchain consensus algorithms based on their historical development and current usage. To demonstrate the relatedness and lineage of distinct algorithms, as well as to support the recapitulation theory, which posits that the evolutionary history of its mainnets is mirrored in the development of an individual consensus algorithm, we present a taxonomy. We have created a comprehensive classification of past and present consensus algorithms that serves to organize this swift consensus algorithm evolution period. By recognizing similarities, we have compiled a list of different verified consensus algorithms and performed clustering on over 38 of these. Our new taxonomic tree presents five taxonomic ranks, including the evolutionary process and decision-making method, as a technique for analyzing correlation. Through the examination of the evolution and utilization of these algorithms, we have developed a systematic and hierarchical taxonomy that enables the grouping of consensus algorithms into distinct categories. The proposed method classifies various consensus algorithms according to taxonomic ranks and aims to reveal the direction of research on the application of blockchain consensus algorithms for each domain.

Securing the Cyber Resilience of a Blockchain-Based Railroad Non-Stop Customs Clearance System.

Current railroad customs clearance systems are problematic in that the movement of trains is occasionally restricted for extended periods during inspections to verify cargo integrity at customs clearance. Consequently, significant human and material resources are consumed to obtain customs clearance to the destination, considering different processes exist for cross-border trade. Therefore, we developed a cross-border blockchain-based non-stop customs clearance (NSCC) system to address these delays and reduce resource consumption for cross-border trains. The integrity, stability, and traceability of blockchain technology are used to construct a stable and reliable customs clearance system to address these problems. The proposed method connects diverse trade and customs clearance agreements in a single blockchain network, which ensures integrity and minimal resource consumption, and includes railroads, freight vehicles, and transit stations in addition to the current customs clearance system. The integrity and confidentiality of customs clearance data are protected using sequence diagrams and the blockchain to strengthen the resilience of the NSCC process against attacks; the blockchain-based NSCC system structurally verifies the attack resilience based on matching sequences. The results confirm that the blockchain-based NSCC system is time- and cost-efficient compared with the current customs clearance system and offers improved attack resilience.

Moutan Cortex Extract Modulates Macrophage Activation via Lipopolysaccharide-Induced Calcium Signaling and ER Stress-CHOP Pathway.

Moutan Cortex, Paeonia suffruticosa root, has long been used as a medicine for the treatment of inflammatory diseases. The aim of this study was to evaluate the modulative properties of Moutan Cortex water extract (CP) on endoplasmic reticulum (ER) stress-related macrophage activation via the calcium-CHOP pathway. RAW 264.7 mouse macrophages were activated by lipopolysaccharide (LPS), and the levels of various inflammatory mediators from RAW 264.7 were evaluated. The multiplex cytokine assay was used to investigate both cytokines and growth factors, and RT-PCR was used to investigate the expressions of inflammation-related genes, such as CHOP. Data represent the levels of NO and cytosolic calcium in LPS-stimulated RAW 264.7 were significantly inhibited by CP as well as hydrogen peroxide (p < 0.05). Minutely, NO production in LPS-stimulated RAW 264.7 incubated with CP at concentrations of 25, 50, 100, and 200 µg/mL for 24 h was 97.32 ± 1.55%, 95.86 ± 2.26%, 94.64 ± 1.83%, and 92.69 ± 2.31% of the control value (LPS only), respectively (p < 0.05). Calcium release in LPS-stimulated RAW 264.7 incubated with CP at concentrations of 25, 50, 100, and 200 µg/mL for 18 h was 95.78 ± 1.64%, 95.41 ± 1.14%, 94.54 ± 2.76%, and 90.89 ± 3.34% of the control value, respectively (p < 0.05). Hydrogen peroxide production in LPS-stimulated RAW 264.7 incubated with CP at concentrations of 25, 50, 100, and 200 µg/mL for 24 h was 79.15 ± 7.16%, 63.83 ± 4.03%, 46.27 ± 4.38%, and 40.66 ± 4.03% of the control value, respectively (p < 0.05). It is interesting that the production of IL-6, TNF-α, G-CSF, MIP-1α, MIP-2, and M-CSF in LPS-stimulated RAW 264.7 were significantly inhibited by CP (p < 0.05), while the production of LIX, LIF, RANTES, and MIP-1ß showed a meaningful decrease. CP at concentrations of 25, 50, 100, and 200 µg/mL significantly reduced the transcription of Chop, Camk2α, NOS, STAT1, STAT3, Ptgs2, Jak2, c-Jun, Fas, c-Fos, TLR3, and TLR9 in LPS-stimulated RAW 264.7 (p < 0.05). CP at concentrations of 25, 50, and 100 µg/mL significantly reduced the phosphorylation of STAT3, p38 MAPK, and IκB-α in LPS-stimulated RAW 264.7 (p < 0.05). These results suggest that CP might modulate macrophage activation via LPS-induced calcium signaling and the ER stress-CHOP pathway.

Myristica fragrans Extract Inhibits Platelet Desialylation and Activation to Ameliorate Sepsis-Associated Thrombocytopenia in a Murine CLP-Induced Sepsis Model.

Sepsis, characterized by an uncontrolled host inflammatory response to infections, remains a leading cause of death in critically ill patients worldwide. Sepsis-associated thrombocytopenia (SAT), a common disease in patients with sepsis, is an indicator of disease severity. Therefore, alleviating SAT is an important aspect of sepsis treatment; however, platelet transfusion is the only available treatment strategy for SAT. The pathogenesis of SAT involves increased platelet desialylation and activation. In this study, we investigated the effects of Myristica fragrans ethanol extract (MF) on sepsis and SAT. Desialylation and activation of platelets treated with sialidase and adenosine diphosphate (platelet agonist) were assessed using flow cytometry. The extract inhibited platelet desialylation and activation via inhibiting bacterial sialidase activity in washed platelets. Moreover, MF improved survival and reduced organ damage and inflammation in a mouse model of cecal ligation and puncture (CLP)-induced sepsis. It also prevented platelet desialylation and activation via inhibiting circulating sialidase activity, while maintaining platelet count. Inhibition of platelet desialylation reduces hepatic Ashwell-Morell receptor-mediated platelet clearance, thereby reducing hepatic JAK2/STAT3 phosphorylation and thrombopoietin mRNA expression. This study lays a foundation for the development of plant-derived therapeutics for sepsis and SAT and provides insights into sialidase-inhibition-based sepsis treatment strategies.

Adjuvanted HIV-1 vaccine promotes antibody-dependent phagocytic responses and protects against heterologous SHIV challenge.

To augment HIV-1 pox-protein vaccine immunogenicity using a next generation adjuvant, a prime-boost strategy of recombinant modified vaccinia virus Ankara and multimeric Env gp145 was evaluated in macaques with either aluminum (alum) or a novel liposomal monophosphoryl lipid A (MPLA) formulation adsorbed to alum, ALFA. Binding antibody responses were robust and comparable between arms, while antibody-dependent neutrophil and monocyte phagocytotic responses were greatly enhanced by ALFA. Per-exposure vaccine efficacy against heterologous tier 2 SHIV mucosal challenge was 90% in ALFA-adjuvanted males (P = 0.002), while alum conferred no protection. Half of the ALFA-adjuvanted males remained uninfected after the full challenge series, which spanned seven months after the last vaccination. Antibody-dependent monocyte and neutrophil phagocytic responses both strongly correlated with protection. Significant sex differences in infection risk were observed, with much lower infection rates in females than males. In humans, MPLA-liposome-alum adjuvanted gp120 also increased HIV-1-specific phagocytic responses relative to alum. Thus, next-generation liposome-based adjuvants can drive vaccine elicited antibody effector activity towards potent phagocytic responses in both macaques and humans and these responses correlate with protection. Future protein vaccination strategies aiming to improve functional humoral responses may benefit from such adjuvants.

Brain cells derived from Alzheimer's disease patients have multiple specific innate abnormalities in energy metabolism.

Altered energy metabolism has been implicated both in aging and the pathogenesis of late-onset Alzheimer's disease (LOAD). However, it is unclear which anomalies are acquired phenotypes and which are inherent and predispose to disease. We report that neural progenitor cells and astrocytes differentiated from LOAD patient-derived induced pluripotent stem cells exhibit multiple inter-related bioenergetic alterations including: changes in energy production by mitochondrial respiration versus glycolysis, as a consequence of alterations in bioenergetic substrate processing and transfer of reducing agents, reduced levels of NAD/NADH, diminished glucose uptake and response rates to insulin (INS)/IGF-1 signaling, decreased INS receptor and glucose transporter 1 densities, and changes in the metabolic transcriptome. Our data confirm that LOAD is a "multi-hit" disorder and provide evidence for innate inefficient cellular energy management in LOAD that likely predisposes to neurodegenerative disease with age. These processes may guide the development and testing of diagnostic procedures or therapeutic agents.

Next Generation Sequencing is a Reliable Tool for Detecting BRCA1/2 Mutations, Including Large Genomic Rearrangements.

BACKGROUND: Next-generation sequencing (NGS) has been implemented as a rapid and cost-effective BRCA1/2 test strategy. The Oncomine™ BRCA Research Assay is an NGS-based tool for simultaneous detection of small-scale mutations and large genomic rearrangements (LGRs). We evaluated this NGS assay using different versions of Ion Reporter™ (IR) software. METHODS: A total of 258 patients with breast, ovarian, primary peritoneal, and fallopian tube cancer, or a family history thereof, were enrolled in the study. The NGS assay was implemented for all samples, and the results were compared with those of Sanger sequencing and MLPA. RESULTS: All small-scale variations in Sanger sequencing were successfully detected by NGS assay. For the detection of LGRs, this assay showed 100% sensitivity from IR v5.10, and the latest version of the software (v5.16) showed the highest sensitivity and specificity. CONCLUSIONS: NGS with an appropriately updated workflow proved reliable for comprehensive BRCA1/2 gene testing, including LGR screening, which could facilitate efficient and accurate decision-making regarding treatment.

Risk Assessment of Mortality in Elderly Individuals: A Nationwide Cohort Study.

INTRODUCTION: There are several methods that are used to predict emergency room visits or rehospitalization for the elderly. However, existing risk assessment models of mortality in elderly people are limited. The purpose of this study was to ascertain the factors that affect all-cause mortality and to show the risk assessment model of mortality in elderly Koreans. METHODS: This was a cohort study conducted using the health checkup data of 246,422 individuals aged ≥60 years, which was provided by the National Health Insurance Service of South Korea between January 1, 2009, and December 31, 2012. The hazard ratios and 95% confidence intervals (CIs) of several conditions and all-cause deaths were estimated using a multivariable Cox proportional hazards model. A nomogram was constructed to visualize the risk factors of mortality; a calibration plot and area under the curve (AUC) were also used to verify the nomogram. RESULTS: Being 85 years or older (100 points) had the greatest influence on all-cause mortality, followed by being underweight (57 points), having more than five chronic diseases (49 points), and ages 78-84 years (45 points); smoking and lack of regular exercise affected mortality to a similar degree. The calibration curves showed good agreement between predictions and observations. The AUC of our nomogram was 0.73 (95% CI: 0.72-0.73). CONCLUSIONS: Our results showed the relationship between each condition and mortality rate among elderly individuals in Korea. Our nomogram showed a satisfactory performance in the assessment of the risk of all-cause mortality in elderly Korean people.

Relationship between Apathy and Subjective Poor Night-time Sleep in de novo, Untreated Parkinson's Disease.

BACKGROUND: Sleep disturbance is one of the most common non-motor symptoms of Parkinson's disease (PD). However, the confounding effects of dopaminergic medication on sleep are a major challenge in understanding the impact of sleep disturbance in PD. We investigated the sleep disturbance and associated clinical features in patients with de novo, untreated PD. METHODS: One-hundred-eight patients with de novo, untreated PD were included. Night sleep disturbance was evaluated using the night sleep subscale of the Scales for Outcomes in Parkinson's Disease (SCOPA-Sleep). Depression, anxiety, and apathy were assessed using the Geriatric Depression Scale (GDS), Beck Anxiety Inventory (BAI), and Apathy Evaluation Scale (AES), respectively. Early perfusion and dopamine transporter imaging of F-18 FP-CIT PET/CT were performed together with statistical parametric mapping analysis. RESULTS: The night sleep SCOPA-Sleep sub-score was correlated with the AES (p = 0.014), BAI (p = 0.014), and GDS (p = 0.023) scores. Patients with poor night sleep were more apathetic (p = 0.013). Additionally, there was increased perfusion in the left posterior cingulate in patients with sleep disturbance and apathy compared to those with sleep disturbance only. CONCLUSIONS: Night sleep disturbance was related to mood disorders, particularly apathy, in patients with de novo, untreated PD.

D-CEWS: DEVS-Based Cyber-Electronic Warfare M&S Framework for Enhanced Communication Effectiveness Analysis in Battlefield.

Currently, in the field of military modernization, tactical networks using advanced unmanned aerial vehicle systems, such as drones, place an emphasis on proactively preventing operational limiting factors produced by cyber-electronic warfare threats and responding to them. This characteristic has recently been highlighted as a key concern in the functioning of modern network-based combat systems in research on combat effect analysis. In this paper, a novel discrete-event-system-specification-based cyber-electronic warfare M&S (D-CEWS) was first proposed as an integrated framework for analyzing communication effects and engagement effects on cyber-electronic warfare threats and related countermeasures that may occur within drones. Accordingly, for the first time, based on communication metrics in tactical ad hoc networks, an analysis was conducted on the engagement effect of blue forces by major wireless threats, such as multi-layered jamming, routing attacks, and network worms. In addition, the correlations and response logics between competitive agents were also analyzed in order to recognize the efficiency of mutual engagements between them based on the communication system incapacitation scenarios for diverse wireless threats. As a result, the damage effect by the cyber-electronic warfare threat, which could not be considered in the existing military M&S, could be calculated according to the PDR (packet delivery ratio) and related malicious pool rate change in the combat area, and the relevance with various threats by a quantifiable mission attribute given to swarming drones could also be additionally secured.