PARP1-TRIM44-MRN loop dictates the response to PARP inhibitors.

PARP inhibitors (PARPi) show selective efficacy in tumors with homologous recombination repair (HRR)-defects but the activation mechanism of HRR pathway in PARPi-treated cells remains enigmatic. To unveil it, we searched for the mediator bridging PARP1 to ATM pathways by screening 211 human ubiquitin-related proteins. We discovered TRIM44 as a crucial mediator that recruits the MRN complex to damaged chromatin, independent of PARP1 activity. TRIM44 binds PARP1 and regulates the ubiquitination-PARylation balance of PARP1, which facilitates timely recruitment of the MRN complex for DSB repair. Upon exposure to PARPi, TRIM44 shifts its binding from PARP1 to the MRN complex via its ZnF UBP domain. Knockdown of TRIM44 in cells significantly enhances the sensitivity to olaparib and overcomes the resistance to olaparib induced by 53BP1 deficiency. These observations emphasize the central role of TRIM44 in tethering PARP1 to the ATM-mediated repair pathway. Suppression of TRIM44 may enhance PARPi effectiveness and broaden their use even to HR-proficient tumors.

Current landscape of research on whitening toothpastes and their effects on dental hard tissue.

PURPOSE: To explore the latest trends in research on whitening toothpaste and to present the issues and future perspectives of these studies. METHODS: An initial PubMed search was performed, followed by a meticulous manual review. A total of 543 papers were initially retrieved, and 54 final research papers were selected and analyzed through a manual review. RESULTS: The number of studies on whitening toothpastes has significantly increased, and while initial studies primarily focused on the efficacy of various whitening toothpastes, recent studies have shifted towards investigating the potential effects on dental hard tissues such as enamel and dentin. Common active ingredients used in these whitening toothpastes include hydrogen peroxide, activated charcoal, and blue covarine. Most studies have used commercial toothpastes with fixed ingredients rather than experimentally manufactured toothpaste, and it was noted that toothpastes from specific major manufacturers were frequently used. CLINICAL SIGNIFICANCE: Whitening toothpastes should be treated as separate entities based on their active ingredients, and more standardized experimental designs are required for better comparisons. Accurate analysis and labeling of other components of toothpaste are also essential.

Differential Impact of WM Load on Attention in Young Adults Versus Children and Adolescents.

Background: This study aimed to examine how concurrent working memory (WM) loads affect selective attention, and to explore developmental differences between young adults and children/adolescents aged 10 to 14 years. Methods: We employed a modified Stroop task with verbal or spatial WM loads to assess their impact on attention. Results: In adults, we found increased Stroop effects when WM load overlapped with target processing and decreased Stroop effects when WM load overlapped with distractor processing. Conversely, in children/adolescents, WM loads did not significantly impact target or distractor processing, indicating no change in Stroop effects under dual-task conditions. Interestingly, results from the correlational analyses revealed that as participants' ages increase, the interference effect under the WM load that shares resources with distractor processing in the attention task decreases. Conclusions: Our findings suggest that the interaction between attention and WM differs across developmental stages. While adults showed distinctive effects of concurrent WM loads on attention processing depending on the cognitive resources utilized, children/adolescents failed to show the interaction between the two cognitive systems. Furthermore, a significant relationship between age and the effects of WM load on attention was observed, providing insights into the development of the interaction between WM and attention.

Comparative Study on Hepatoprotective Effects of Traditional Herbs, Roots of Angelica gigas Nakai, Glycyrrhiza uralensis Fischer, Zizyphus jujuba Mill., and Fruits of Paeonia lactiflora Pall., on Ethanol-Induced Liver Injury in Mice.

Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease, with few effective treatments besides alcohol abstinence. Angelicae Gigantis Radix (AG), Glycyrrhizae Radix et Rhizoma (GR), Paeoniae Radix (PR), and Zizyphi Fructus (ZF) are traditional herbs used to treat various ailments, including liver diseases. While several studies have reported the beneficial effects of GR on ALD, the effects of AG, PR, and ZF remain underexplored. Therefore, their efficacy and mechanisms against ALD were investigated using an alcohol-related liver injury model. The model was induced by ethanol gavage in C57BL/6J mice for 14 days, followed by oral administration of AG, GR, PR, and ZF one hour post-induction. The administration of these herbs reduced liver weight, and improved serum biomarkers of liver injury (ALT, AST, albumin). The herbs enhanced hepatic antioxidant capacity (GSH, SOD, catalase) and suppressed the production of proinflammatory cytokines (TNF-α, IL-1ß) and apoptotic changes (caspase-3). The mechanisms of action involved lipid-lowering gene modulation through regulation of the cytochrome P450 2E1/Sirtuin 1/Nrf2 pathways. Histopathological and immunohistochemical analyses revealed that these herbs attenuated hepatocyte damage and steatosis via antioxidant, anti-inflammatory, and antiapoptotic effects. These findings suggest that traditional herbs, particularly AG, could be promising alternative therapies for treating ALD.

Intraluminal Contrast-Enhanced Ultrasonography Application in Dogs and Cats.

Administering intraluminal fluid can improve the acoustic window for the visualization of the lumen and wall layers in the cavitary organs. Microbubbles in ultrasound contrast agents can also be used for intracavitary applications to enhance visualization of the lesion in human patients. However, there was no literature extending the clinical application of intraluminal contrast-enhanced ultrasonography (CEUS) to patients with naturally occurring diseases in veterinary medicine. This case series aims to describe the detailed application and diagnostic value of intraluminal CEUS in six clinical cases with naturally occurring gastrointestinal (GI) and urinary tract diseases.

Lactobacillus plantarum NCHBL-004 modulates high-fat diet-induced weight gain and enhances GLP-1 production for blood glucose regulation.

OBJECTIVES: This study investigated the therapeutic potential of Lactobacillus plantarum NCHBL-004 (NCHBL-004) in the treatment of obesity and associated metabolic disorders. METHODS: Mice were fed either a normal diet (ND) or a high-fat diet (HFD) with oral administration of NCHBL-004. After euthanasia, blood, liver and adipose tissue were collected. Furthermore, the microbiome and short-chain fatty acids (SCFAs) were analyzed from feces. RESULTS: Oral administration of live NCHBL-004 to mice fed a HFD resulted in notable reductions in weight gain, improvements in glucose metabolism, and maintenance of balanced lipid levels. A comparative analysis with other Lactobacillus strains highlighted the superior efficacy of NCHBL-004. Moreover, heat-killed NCHBL-004 demonstrated beneficial effects similar to those of live NCHBL-004. Additionally, administration of live NCHBL-004 induced glucagon-like peptide 1 (GLP-1) production and increased the levels of short-chain fatty acids (SCFAs), including acetate and propionate, in feces, positively influencing liver lipid metabolism and mitigating inflammation. Consistent with this, analysis of the gut microbiome following NCHBL-004 administration showed increases in SCFA-producing microbes with increased proportions of Lactobacillus spp. and a significant increase in the proportion of microbes capable of promoting GLP-1 secretion. CONCLUSIONS: These findings underscore the potential of both live and inactivated NCHBL-004 as potential therapeutic approaches to managing obesity and metabolic disorders, suggesting avenues for further investigation and clinical applications.

A blended genome and exome sequencing method captures genetic variation in an unbiased, high-quality, and cost-effective manner.

We deployed the Blended Genome Exome (BGE), a DNA library blending approach that generates low pass whole genome (1-4× mean depth) and deep whole exome (30-40× mean depth) data in a single sequencing run. This technology is cost-effective, empowers most genomic discoveries possible with deep whole genome sequencing, and provides an unbiased method to capture the diversity of common SNP variation across the globe. To evaluate this new technology at scale, we applied BGE to sequence >53,000 samples from the Populations Underrepresented in Mental Illness Associations Studies (PUMAS) Project, which included participants across African, African American, and Latin American populations. We evaluated the accuracy of BGE imputed genotypes against raw genotype calls from the Illumina Global Screening Array. All PUMAS cohorts had R 2 concordance ≥95% among SNPs with MAF≥1%, and never fell below ≥90% R 2 for SNPs with MAF<1%. Furthermore, concordance rates among local ancestries within two recently admixed cohorts were consistent among SNPs with MAF≥1%, with only minor deviations in SNPs with MAF<1%. We also benchmarked the discovery capacity of BGE to access protein-coding copy number variants (CNVs) against deep whole genome data, finding that deletions and duplications spanning at least 3 exons had a positive predicted value of ~90%. Our results demonstrate BGE scalability and efficacy in capturing SNPs, indels, and CNVs in the human genome at 28% of the cost of deep whole-genome sequencing. BGE is poised to enhance access to genomic testing and empower genomic discoveries, particularly in underrepresented populations.

Multivariate genomic analysis of 5 million people elucidates the genetic architecture of shared components of the metabolic syndrome.

Metabolic syndrome (MetS) is a complex hereditary condition comprising various metabolic traits as risk factors. Although the genetics of individual MetS components have been investigated actively through large-scale genome-wide association studies, the conjoint genetic architecture has not been fully elucidated. Here, we performed the largest multivariate genome-wide association study of MetS in Europe (nobserved = 4,947,860) by leveraging genetic correlation between MetS components. We identified 1,307 genetic loci associated with MetS that were enriched primarily in brain tissues. Using transcriptomic data, we identified 11 genes associated strongly with MetS. Our phenome-wide association and Mendelian randomization analyses highlighted associations of MetS with diverse diseases beyond cardiometabolic diseases. Polygenic risk score analysis demonstrated better discrimination of MetS and predictive power in European and East Asian populations. Altogether, our findings will guide future studies aimed at elucidating the genetic architecture of MetS.

Postmortem-Derived Exosomal MicroRNA 486-5p as Potential Biomarkers for Ischemic Heart Disease Diagnosis.

Exosomes are nanovesicles 30-150 nm in diameter released extracellularly. Those isolated from human body fluids reflect the characteristics of their cells or tissues of origin. Exosomes carry extensive biological information from their parent cells and have significant potential as biomarkers for disease diagnosis and prognosis. However, there are limited studies utilizing exosomes in postmortem diagnostics. In this study, we extended our initial research which identified the presence and established detection methodologies for exosomes in postmortem fluids. We analyzed exosomal miRNA extracted from plasma and pericardial fluid samples of a control group (n = 13) and subjects with acute myocardial infarction (AMI; n = 24). We employed next-generation sequencing (NGS) to investigate whether this miRNA could serve as biomarkers for coronary atherosclerosis leading to acute myocardial infarction. Our analysis revealed 29 miRNAs that were differentially expressed in the AMI group compared to the control group. Among these, five miRNAs exhibited more than a twofold increase in expression across all samples from the AMI group. Specifically, miR-486-5p levels were significantly elevated in patients with high-grade (type VI or above) atherosclerotic plaques, as per the American Heart Association criteria, highlighting its potential as a predictive biomarker for coronary atherosclerosis progression. Our results indicate that postmortem-derived exosomal microRNAs can serve as potential biomarkers for various human diseases, including cardiovascular disorders. This finding has profound implications for forensic diagnostics, a field critically lacking diagnostic markers.

HER4 is a high-affinity dimerization partner for all EGFR/HER/ErbB family proteins.

Human epidermal growth factor receptors (HER)-also known as EGFR or ErbB receptors-are a subfamily of receptor tyrosine kinases (RTKs) that play crucial roles in cell growth, division, and differentiation. HER4 (ErbB4) is the least studied member of this family, partly because its expression is lower in later stages of development. Recent work has suggested that HER4 can play a role in metastasis by regulating cell migration and invasiveness; however, unlike EGFR and HER2, the precise role that HER4 plays in tumorigenesis is still unresolved. Early work on HER family proteins suggested that there are direct interactions between the four members, but to date, there has been no single study of all four receptors in the same cell line with the same biophysical method. Here, we quantitatively measure the degree of association between HER4 and the other HER family proteins in live cells with a time-resolved fluorescence technique called pulsed interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS). PIE-FCCS is sensitive to the oligomerization state of membrane proteins in live cells, while simultaneously measuring single-cell protein expression levels and diffusion coefficients. Our PIE-FCCS results demonstrate that HER4 interacts directly with all HER family members in the cell plasma membrane. The interaction between HER4 and other HER family members intensified in the presence of a HER4-specific ligand. Our work suggests that HER4 is a preferred dimerization partner for all HER family proteins, even in the absence of ligands.

Operating Mechanism Principles and Advancements for Halide Perovskite-Based Memristors and Neuromorphic Devices.

With the advent of the generation of artificial intelligence (AI) based on big data-processing technologies, next-generation memristor and memristive neuromorphic devices have been actively studied with great interest to overcome the von Neumann bottleneck limits. Among various candidates, halide perovskites (HPs) have been in the spotlight as potential candidates for these devices due to their unique switching characteristics with low energy consumption and flexible integration compatibility across various sources for scalability. We outline the characteristics and operating principles of HP-based memristors and their neuromorphic devices. We explain filamentary- and interface-type switching according to the type of conducting pathway occurring inside the active HP layer and the operating mechanisms depending on the species that make up this conducting pathway. We summarize the types and mechanisms of current changes beneficial for neuromorphic device applications and finally organize various suggested analysis tools and physical models to enable experimental determination of switching mechanisms from various perspectives.

Who is performing the driving tasks after interventions? Investigating drivers' understanding of mode transition logic in automated vehicles.

Mode awareness is important for the safe use of automated vehicles, yet drivers' understanding of mode transitions has not been sufficiently investigated. In this study, we administered an online survey to 838 respondents to examine their understanding of control responsibilities in partial and conditional driving automation with four types of interventions (brake pedal, steering wheel, gas pedal, and take-over request). Results show that most drivers understand that they are responsible for speed and distance control after brake pedal interventions and steering control after steering wheel interventions. However, drivers have mixed responses regarding the responsibility for speed and distance control after steering wheel interventions and the responsibility for steering control after gas pedal interventions. With a higher automation level (conditional driving automation), drivers expect automation to remain responsible more often compared to a lower automation level (partial driving automation). Regarding Hands-on requirements, more than 99% of respondents answered that drivers would keep their hands on the steering wheel after all intervention types in partial automation, while 60-95% would place their hands on the wheel after various intervention types in conditional automation. A misalignment between actual logic and drivers' expectations regarding control responsibilities is observed by comparing survey responses to the mode transition logic of commercial partially automated vehicles. To resolve confusion about control responsibilities and ensure consistent expectations, we propose implementing a consistent mode design and providing enhanced information to drivers.

Highly Functionalized SuFEx-able Hub Bearing All-Carbon Quaternary Center via Rapid Brønsted Superbase Catalysis.

A rapid Brønsted superbase catalysis for highly functionalized sulfur(VI)-fluoride exchange (SuFEx) hubs bearing all-carbon quaternary centers was developed. Remarkable functional group tolerance toward esters and nitriles was achieved by Michael addition of cyanoacetate derivatives to ethenesulfonyl fluoride with low catalyst loadings (∼0.5 mol %) within a short reaction time (0.5-30 min). Gram-scalability, water tolerance, and compatibility in polymeric catalysis showcase its unique practicability. SuFEx click conjugations were demonstrated using various amines, including DNA-tethered biomolecules.

Secure Triggering Frame-Based Dynamic Power Saving Mechanism against Battery Draining Attack in Wi-Fi-Enabled Sensor Networks.

Wireless local area networks (WLANs) have recently evolved into technologies featuring extremely high throughput and ultra-high reliability. As WLANs are predominantly utilized in Internet of Things (IoT) and Wi-Fi-enabled sensor applications powered by coin cell batteries, these high-efficiency, high-performance technologies often cause significant battery depletion. The introduction of the trigger frame-based uplink transmission method, designed to enhance network throughput, lacks adequate security measures, enabling attackers to manipulate trigger frames. Devices receiving such frames must respond immediately; however, if a device receives a fake trigger frame, it fails to enter sleep mode, continuously sending response signals and thereby increasing power consumption. This problem is specifically acute in next-generation devices that support multi-link operation (MLO), capable of simultaneous transmission and reception across multiple links, rendering them more susceptible to battery draining attacks than conventional single-link devices. To address this, this paper introduces a Secure Triggering Frame-Based Dynamic Power Saving Mechanism (STF-DPSM) specifically designed for multi-link environments. Experimental results indicate that even in a multi-link environment with only two links, the STF-DPSM improves energy efficiency by an average of approximately 55.69% over conventional methods and reduces delay times by an average of approximately 44.7% compared with methods that consistently utilize encryption/decryption and integrity checks.

Influence of coffee characteristics on tooth discoloration.

PURPOSE: To evaluate the impact of coffee attributes on tooth discoloration, emphasizing the importance of potential factors such as serving temperature, bean variety, and chlorogenic acid (CGA) content. METHODS: Coffee preparation involved the extraction of espresso from four types of roasted beans (Vietnam Robusta, Uganda Robusta, Ethiopia Yirgacheffe Arabica, and Colombia Supremo Arabica), followed by chlorogenic content analysis using high-performance liquid chromatography. Bovine tooth enamel specimens were carefully prepared and stained with coffee (hot and iced), with a color assessment conducted at different time intervals (3, 9, 24, 48, and 72 hours). The Vickers hardness tester was employed to ensure specimen quality, while spectrophotometry aided in color analysis using the CIEDE2000 formula. RESULTS: The results revealed varying effects of serving temperature, bean type, and CGA content on tooth discoloration. It was demonstrated that perceptible color differences occur after a 3-hour immersion in coffee, with hot coffee showing higher staining potential compared to iced variations. Furthermore, chlorogenic acid content and bean type significantly affected tooth discoloration, with higher chlorogenic acid levels associated with increased staining. Notably, Robusta coffee showed less discoloration compared to Arabica, potentially due to differences in pH levels. CLINICAL SIGNIFICANCE: The findings provide valuable insights for both dental practitioners and coffee consumers, assisting in making informed decisions regarding coffee intake and oral hygiene.

Microbial assemblages and associated biogeochemical processes in Lake Bonney, a permanently ice-covered lake in the McMurdo Dry Valleys, Antarctica.

BACKGROUND: Lake Bonney, which is divided into a west lobe (WLB) and an east lobe (ELB), is a perennially ice-covered lake located in the McMurdo Dry Valleys of Antarctica. Despite previous reports on the microbial community dynamics of ice-covered lakes in this region, there is a paucity of information on the relationship between microbial genomic diversity and associated nutrient cycling. Here, we applied gene- and genome-centric approaches to investigate the microbial ecology and reconstruct microbial metabolic potential along the depth gradient in Lake Bonney. RESULTS: Lake Bonney is strongly chemically stratified with three distinct redox zones, yielding different microbial niches. Our genome enabled approach revealed that in the sunlit and relatively freshwater epilimnion, oxygenic photosynthetic production by the cyanobacterium Pseudanabaena and a diversity of protists and microalgae may provide new organic carbon to the environment. CO-oxidizing bacteria, such as Acidimicrobiales, Nanopelagicales, and Burkholderiaceae were also prominent in the epilimnion and their ability to oxidize carbon monoxide to carbon dioxide may serve as a supplementary energy conservation strategy. In the more saline metalimnion of ELB, an accumulation of inorganic nitrogen and phosphorus supports photosynthesis despite relatively low light levels. Conversely, in WLB the release of organic rich subglacial discharge from Taylor Glacier into WLB would be implicated in the possible high abundance of heterotrophs supported by increased potential for glycolysis, beta-oxidation, and glycoside hydrolase and may contribute to the growth of iron reducers in the dark and extremely saline hypolimnion of WLB. The suboxic and subzero temperature zones beneath the metalimnia in both lobes supported microorganisms capable of utilizing reduced nitrogens and sulfurs as electron donors. Heterotrophs, including nitrate reducing sulfur oxidizing bacteria, such as Acidimicrobiales (MAG72) and Salinisphaeraceae (MAG109), and denitrifying bacteria, such as Gracilimonas (MAG7), Acidimicrobiales (MAG72) and Salinisphaeraceae (MAG109), dominated the hypolimnion of WLB, whereas the environmental harshness of the hypolimnion of ELB was supported by the relatively low in metabolic potential, as well as the abundance of halophile Halomonas and endospore-forming Virgibacillus. CONCLUSIONS: The vertical distribution of microbially driven C, N and S cycling genes/pathways in Lake Bonney reveals the importance of geochemical gradients to microbial diversity and biogeochemical cycles with the vertical water column.

Transcriptomic heterogeneity of EGFR-mutant non-small cell lung cancer evolution towards small cell lung cancer.

PURPOSE: Histological transformation from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a key mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs). However, transcriptomic changes between NSCLC and transformed SCLC (t-SCLC) remain unexplored. EXPERIMENTAL DESIGN: We conducted whole transcriptome analysis of 59 regions of interest (ROIs) through the spatial profiling of FFPE tissues obtained from ten patients (lung adenocarcinoma, 22; combined SCLC/NSCLC, 7; t-SCLC, 30 ROIs). Transcriptomic profiles and differentially expressed genes (DEGs) were compared between pre- and post-transformed tumors. RESULTS: Following EGFR-TKI treatment, 93.7% (15/16) of transformed-SCLC (t-SCLC) components evolved into neuroendocrine-high subtypes (SCLC-A or SCLC-N). The transition to t-SCLC occurred regardless of EGFR-TKI treatment and EGFR mutational status, with a notable decrease in EGFR expression (P < 0.001) at both mRNA and protein levels. Pathway analysis revealed that gene overexpression was related to epigenetic alterations in t-SCLC. Interestingly, Histone deacetylase (HDAC) inhibitors restored EGFR expression in SNU-2962A cells and their organoid model. The synergistic effects of third-generation EGFR-TKI osimertinib and the HDAC inhibitor fimepinostat were validated in both in vitro and in vivo models. CONCLUSIONS: Our study demonstrated most t-SCLC showed neuronal subtypes with low EGFR expression. DEGs analysis and t-SCLC preclinical models identified an epigenetic modifier as a promising treatment strategy for t-SCLC.

Push-Pull Mechanism of Attention and Emotion in Children with Attention Deficit Hyperactivity Disorder.

Background/Objectives: While deficits in executive attention and alerting systems in children with attention deficit hyperactivity disorder (ADHD) are well-documented, findings regarding orienting attention in ADHD have been inconsistent. The current study investigated the mechanism of attentional orienting in children with ADHD by examining their attentional bias towards threatening stimuli. Furthermore, we explored the modulating role of anxiety levels in ADHD on this attentional bias. Methods: In Experiment 1, 20 children with ADHD and 26 typically developing children (TDC) performed a continuous performance task that included task-irrelevant distractions consisting of angry faces and neutral places. In Experiment 2, 21 children with ADHD and 25 TDC performed the same task, but with angry and neutral faces as distractors. To measure children's anxiety levels, the State-Trait Anxiety Inventory was administered before each experiment. Results: In Experiment 1, results revealed no attentional bias effects in children with ADHD, whereas TDC exhibited attentional capture effects by both types of distractors. However, in Experiment 2, ADHD children demonstrated an attentional bias towards angry faces, which revealed a significant positive correlation with their trait anxiety levels (r = 0.61, p < 0.05). Further analyses combining all ADHD children showed that trait anxiety levels in Experiment 2 were significantly higher than those in Experiment 1. Finally, a significant positive correlation was found between anxiety levels and attentional bias towards angry faces in all ADHD children (r = 0.36, p < 0.01). Conclusions: Children with ADHD exhibited atypical attentional-orienting effects to threats, and their levels of trait anxiety appeared to modulate such attentional-orienting mechanisms.

Electrochemical Circuit Model Based State of Health Prognostics for Evaluation of Reusability of Lithium-Ion Batteries from Electric Vehicle.

For the purpose of predicting the state of health of already used lithium-ion batteries from 85 kWh electric vehicles, a simplified equivalent circuit model is utilized to estimate the electrochemical time constant from constant current discharge profiles. The grading process among as-obtained LIB cells is classified into three level types according to the remaining capacity and direct current resistance. Theoretically, the logarithmic equation describing cycling behavior is derived and utilized in the prediction of the state of health of the used cells. After the selection of the electrochemical time constant obtained from the best-fitting results in constant current discharge data, the suitable cycle number until the 20th cycle was selected for the prediction of the state of health after the 250th cycling data, which revealed that a narrow error range below 5% was for high and medium battery grades. Also, this error range became abruptly wider in lowest grade batteries, indicating that our proposed model for cycling behavior was highly useful in the prediction of the future state of health of the used batteries.