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Insider threats are malicious activities by authorized users, such as theft of intellectual property or security information, fraud, and sabotage. Although the number of insider threats is much lower than external network attacks, insider threats can cause extensive damage. As insiders are very familiar with an organization’s system, it is very difficult to detect their malicious behavior. Traditional insider-threat detection methods focus on rule-based approaches built by domain experts, but they are neither flexible nor robust. In this paper, we propose insider-threat detection methods based on user behavior modeling and anomaly detection algorithms. Based on user log data, we constructed three types of datasets: user’s daily activity summary, e-mail contents topic distribution, and user’s weekly e-mail communication history. Then, we applied four anomaly detection algorithms and their combinations to detect malicious activities. Experimental results indicate that the proposed framework can work well for imbalanced datasets in which there are only a few insider threats and where no domain experts’ knowledge is provided.

Precocious puberty is characterized by early sexual maturation in children before 8 years in girls and 9 years in boys. While puberty is initiated by the activation of the hypothalamic–pituitary–gonadal axis, precise mechanisms triggering the early activation of this axis in children with central precocious puberty (CPP) remain elusive. Here, we aimed to identify variables that may influence the risk of CPP. This retrospective cohort study utilized data from the Korean National Health Insurance Service and National Health Screening Program for Infants and Children and included 43,952 children with CPP and 854,749 controls. Participants were followed up until 2020 for CPP development to determine their height, weight, and head circumference measurements, as well as evaluate their physiological, emotional, cognitive, and social development. The birth weights for boys and girls with CPP were 0.09 and 0.06 kg lower than those of controls, respectively. Breastfeeding rates for children with CPP were lower than those for controls. Children with low birth weights (boys: odds ratio [OR] = 1.71, P  < 0.0001; girls: OR 1.30, P  < 0.0001) and those who were overweight (boys: OR 1.33, P  = 0.0006; girls: OR 1.30, P  < 0.0001) or obese (boys: OR 1.60, P  < 0.0001; girls: OR 1.14, P  < 0.0001) were more likely to develop CPP. Breastfeeding exerted a significant protective effect against CPP in girls (OR 0.95, P  = 0.0003). Low birth weight and high body mass index were associated with CPP development.

Background Cancer remains a leading global cause of mortality, responsible for nearly 10 million deaths in 2020. Given the country’s low birth rate and aging population, the escalating cancer burden poses significant challenges to its healthcare systems. This study aimed to investigate the relationship between lifestyle risk factors and cancer case fatality, emphasizing the collective impact of these factors through a prevention index at the regional level. Methods The study focused on ten cancer types, categorizing counties into three levels of cancer incidence rates using group-based trajectory modeling to identify disparities in patterns and levels among groups. Additionally, we segmented the proportions of obesity prevalence, average daily per capita smoking amount, prevalence of smoking, prevalence of high-risk alcohol consumption, prevalence of hypertension diagnosis, prevalence of diabetes diagnosis, and cancer case fatality into three groups through group-based trajectory modeling. Cox proportional hazard models were employed to evaluate the hazard ratios (HR) for cancer case fatality, adjusting for age, sex, income level, and cancer stage. Results The study population comprised 294,070 cancer patients, with thyroid, stomach, colorectal, breast, and lung cancers being the most common. The prevention index (PI) levels, calculated from six primary prevention indicators, were categorized into High, Medium, and Low grades. Counties with higher PI levels (H) exhibited significantly lower cancer case fatality among cancer patients compared to those with lower PI levels (L). Across all cancer types, females had lower cancer case fatality compared to males, higher age was linked to higher cancer case fatality, advanced stage cases had the highest cancer case fatality, and the highest income quintile consistently showed the lowest cancer case fatality. Conclusions The study highlights the significant inverse relationship between primary prevention indicator levels and cancer case fatality. Higher scores on primary prevention indicators are associated with lower cancer mortality among cancer patients for various cancer types, underscoring the importance of comprehensive, community-based prevention strategies in mitigating cancer risk and improving public health outcomes in South Korea.

With regard to the parameterized projection-based reduced-order model, it is significant to consider the computational efficiency as well as its capability for the parametric variation. The proposed approach is based on the online adaptive procedure to improve the accuracy and stability of the reduced-order model. Achieving efficient computation in online adaptation, a matrix version of the discrete empirical interpolation method is employed to approximate the nonlinear finite element matrix, independently. The proposed approach is applied to analysis of a structure with geometric and material nonlinearities. As a result, the computational efficiency during the offline/online steps of the proposed approach is significantly improved, compared to other existing approaches. Moreover, within the present numerical examinations, it is found that the proposed approach is capable of accurately addressing broad parametric variations by using only ten percent of the number of data used in the conventional ROM from the preliminary computation.

Pyrimidine is a privileged scaffold in many synthetic compounds exhibiting diverse pharmacological activities, and is used for therapeutic applications in a broad spectrum of human diseases. In this study, we prepared a small set of pyrimidine libraries based on the structure of two hit compounds that were identified through the screening of an in-house library in order to identify an inhibitor of anoctamin 1 (ANO1). ANO1 is amplified in various types of human malignant tumors, such as head and neck, parathyroid, and gastrointestinal stromal tumors, as well as in breast, lung, and prostate cancers. After initial screening and further structure optimization, we identified Aa3 as a dose-dependent ANO1 blocker. This compound exhibited more potent anti-cancer activity in the NCI-H460 cell line, expressing high levels of ANO1 compared with that in A549 cells that express low levels of ANO1. Our results open a new direction for the development of small-molecule ANO1 blockers composed of a pyrimidine scaffold and a nitrogen-containing heterocyclic moiety, with drug-like properties.

Heat exchangers are usually designed using a sophisticated process of trial-and-error to find proper values of unknown parameters which satisfy given requirements. Recently, the design of heat exchangers using evolutionary optimization algorithms has received attention. The major aim of the present study is to propose an improved Gaussian quantum-behaved particle swarm optimization (GQPSO) algorithm for enhanced optimization performance and its verification through application to a multivariable thermal-economic optimization problem of a crossflow plate–fin heat exchanger (PFHE). Three single objective functions: the number of entropy generation units (NEGUs), total annual cost (TAC), and heat exchanger surface area (A), were minimized separately by evaluating optimal values of seven unknown variables using four different PSO-based methods. By comparing the obtained best fitness values, the improved GQPSO approach could search quickly for better global optimal solutions by preventing particles from falling to the local minimum due to its modified local attractor scheme based on the Gaussian distributed random numbers. For example, the proposed GQPSO could predict further improved best fitness values of 40% for NEGUs, 17% for TAC, and 4.5% for A, respectively. Consequently, the present study suggests that the improved GQPSO approach with the modified local attractor scheme can be efficient in rapidly finding more suitable solutions for optimizing the thermal-economic problem of the crossflow PFHE.

MicroRNAs (miRNAs) are small, yet profoundly influential, non-coding RNAs that base-pair with mRNAs to induce RNA silencing. Although the basic principles of miRNA biogenesis and function have been established, recent breakthroughs have yielded important new insights into the molecular mechanisms of miRNA biogenesis. In this Review, we discuss the metazoan miRNA biogenesis pathway step-by-step, focusing on the key biogenesis machinery, including the Drosha–DGCR8 complex (Microprocessor), exportin-5, Dicer and Argonaute. We also highlight newly identified cis -acting elements and their impact on miRNA maturation, informed by advanced high-throughput and structural studies, and discuss recently discovered mechanisms of clustered miRNA processing, target recognition and target-directed miRNA decay (TDMD). Lastly, we explore multiple regulatory layers of miRNA biogenesis, mediated by RNA–protein interactions, miRNA tailing (uridylation or adenylation) and RNA modifications. MicroRNAs (miRNAs) are small non-coding RNAs that induce RNA silencing. Advances in high-throughput and structural studies have provided new insights into animal miRNA biogenesis mediated by RNA–protein interactions, miRNA tailing (uridylation or adenylation) and RNA modifications, and have increased our understanding of miRNA target recognition and target-directed miRNA decay.

RNA silencing relies on specific and efficient processing of double-stranded RNA by Dicer, which yields microRNAs (miRNAs) and small interfering RNAs (siRNAs) 1 , 2 . However, our current knowledge of the specificity of Dicer is limited to the secondary structures of its substrates: a double-stranded RNA of approximately 22 base pairs with a 2-nucleotide 3′ overhang and a terminal loop 3 – 11 . Here we found evidence pointing to an additional sequence-dependent determinant beyond these structural properties. To systematically interrogate the features of precursor miRNAs (pre-miRNAs), we carried out massively parallel assays with pre-miRNA variants and human DICER (also known as DICER1). Our analyses revealed a deeply conserved cis -acting element, termed the ‘GYM motif’ (paired G, paired pyrimidine and mismatched C or A), near the cleavage site. The GYM motif promotes processing at a specific position and can override the previously identified ‘ruler’-like counting mechanisms from the 5′ and 3′ ends of pre-miRNA 3 – 6 . Consistently, integrating this motif into short hairpin RNA or Dicer-substrate siRNA potentiates RNA interference. Furthermore, we find that the C-terminal double-stranded RNA-binding domain (dsRBD) of DICER recognizes the GYM motif. Alterations in the dsRBD reduce processing and change cleavage sites in a motif-dependent fashion, affecting the miRNA repertoire in cells. In particular, the cancer-associated R1855L substitution in the dsRBD strongly impairs GYM motif recognition. This study uncovers an ancient principle of substrate recognition by metazoan Dicer and implicates its potential in the design of RNA therapeutics. Massively parallel assays reveal a highly conserved sequence motif termed the GYM motif, which potentiates RNA interference by directing Dicer-mediated small RNA processing.

Dicer has a key role in small RNA biogenesis, processing double-stranded RNAs (dsRNAs) 1 , 2 . Human DICER (hDICER, also known as DICER1) is specialized for cleaving small hairpin structures such as precursor microRNAs (pre-miRNAs) and has limited activity towards long dsRNAs—unlike its homologues in lower eukaryotes and plants, which cleave long dsRNAs. Although the mechanism by which long dsRNAs are cleaved has been well documented, our understanding of pre-miRNA processing is incomplete because structures of hDICER in a catalytic state are lacking. Here we report the cryo-electron microscopy structure of hDICER bound to pre-miRNA in a dicing state and uncover the structural basis of pre-miRNA processing. hDICER undergoes large conformational changes to attain the active state. The helicase domain becomes flexible, which allows the binding of pre-miRNA to the catalytic valley. The double-stranded RNA-binding domain relocates and anchors pre-miRNA in a specific position through both sequence-independent and sequence-specific recognition of the newly identified ‘GYM motif’ 3 . The DICER-specific PAZ helix is also reoriented to accommodate the RNA. Furthermore, our structure identifies a configuration of the 5′ end of pre-miRNA inserted into a basic pocket. In this pocket, a group of arginine residues recognize the 5′ terminal base (disfavouring guanine) and terminal monophosphate; this explains the specificity of hDICER and how it determines the cleavage site. We identify cancer-associated mutations in the 5′ pocket residues that impair miRNA biogenesis. Our study reveals how hDICER recognizes pre-miRNAs with stringent specificity and enables a mechanistic understanding of hDICER-related diseases. The active-state structure of human DICER bound to pre-miRNA reveals the structural basis for the specificity of DICER in how it selects substrates in a sequence dependent manner, and sheds light on DICER-related diseases.

Objective Our goal was to explore racial socialization practices in Asian American families during a time of heightened racial tension. Background Asian Americans hold a complex racial position in the United States, made even more complicated by an increase in public protests regarding socioracial injustices in the United States experienced by racial minority groups. Discussions about race and ethnicity occur within Asian American families but often focus on cultural heritage rather than awareness of discrimination and the historical roots of racism. Method Our study used an inductive–deductive thematic analysis to collect data from 12 Asian American young adults. Semistructured interviews queried participants' experiences with racial socialization in their nuclear families and their own racial identity. Findings Qualitative analysis revealed the following themes: (a) Participants received limited messages regarding racial issues, (b) participants engaged in “bottom‐up” racial socialization and taught their parents about race, and (c) participants felt left out of society's racial dialogue. Conclusion During this time of heightened racial tension, Asian American young adults struggle to find their place, despite wanting to participate in community building. Implications Without strong Asian American racial socialization practices in families, young adults must educate themselves and initiate racial meaning‐making in their families.