Gene Expression and Metabolome Analysis Reveals Anti-Inflammatory Impacts of 11,17diHDoPE on PM10-Induced Mouse Lung Inflammation.

Oxylipins, the metabolites of polyunsaturated fatty acids, are vital in regulating cell proliferation and inflammation. Among these oxylipins, specialized pro-resolving mediators notably contribute to inflammation resolution. Previously, we showed that the specialized pro-resolving mediators isomer 11,17dihydroxy docosapentaenoic acid (11,17diHDoPE) can be synthesized in bacterial cells and exhibits anti-inflammatory effects in mammalian cells. This study investigates the in vivo impact of 11,17diHDoPE in mice exposed to particulate matter 10 (PM10). Our results indicate that 11,17diHDoPE significantly mitigates PM10-induced lung inflammation in mice, as evidenced by reduced pro-inflammatory cytokines and pulmonary inflammation-related gene expression. Metabolomic analysis reveals that 11,17diHDoPE modulates inflammation-related metabolites such as threonine, 2-keto gluconic acid, butanoic acid, and methyl oleate in lung tissues. In addition, 11,17diHDoPE upregulates the LA-derived oxylipin pathway and downregulates arachidonic acid- and docosahexaenoic acid-derived oxylipin pathways in serum. Correlation analyses between gene expression and metabolite changes suggest that 11,17diHDoPE alleviates inflammation by interfering with macrophage differentiation. These findings underscore the in vivo role of 11,17diHDoPE in reducing pulmonary inflammation, highlighting its potential as a therapeutic agent for respiratory diseases.

3C methods in cancer research: recent advances and future prospects.

In recent years, Hi-C technology has revolutionized cancer research by elucidating the mystery of three-dimensional chromatin organization and its role in gene regulation. This paper explored the impact of Hi-C advancements on cancer research by delving into high-resolution techniques, such as chromatin loops, structural variants, haplotype phasing, and extrachromosomal DNA (ecDNA). Distant regulatory elements interact with their target genes through chromatin loops. Structural variants contribute to the development and progression of cancer. Haplotype phasing is crucial for understanding allele-specific genomic rearrangements and somatic clonal evolution in cancer. The role of ecDNA in driving oncogene amplification and drug resistance in cancer cells has also been revealed. These innovations offer a deeper understanding of cancer biology and the potential for personalized therapies. Despite these advancements, challenges, such as the accurate mapping of repetitive sequences and precise identification of structural variants, persist. Integrating Hi-C with multiomics data is key to overcoming these challenges and comprehensively understanding complex cancer genomes. Thus, Hi-C is a powerful tool for guiding precision medicine in cancer research and treatment.

MMPP is a novel VEGFR2 inhibitor that suppresses angiogenesis via VEGFR2/AKT/ERK/NF-κB pathway.

Many types of cancer are associated with excessive angiogenesis. Anti-angiogenic treatment is an effective strategy for treating solid cancers. This study aimed to demonstrate the inhibitory effects of (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP) in VEGFA-induced angiogenesis. The results indicated that MMPP effectively suppressed various angiogenic processes, such as cell migration, invasion, tube formation, and sprouting of new vessels in human umbilical vein endothelial cells (HUVECs) and mouse aortic ring. The inhibitory mechanism of MMPP on angiogenesis involves targeting VEGFR2. MMPP showed high binding affinity for the VEGFR2 ATP-binding domain. Additionally, MMPP improved VEGFR2 thermal stability and inhibited VEGFR2 kinase activity, suppressing the downstream VEGFR2/AKT/ERK pathway. MMPP attenuated the activation and nuclear translocation of NF-κB, and it downregulated NF-κB target genes such as VEGFA, VEGFR2, MMP2, and MMP9. Furthermore, conditioned medium from MMPP-treated breast cancer cells effectively inhibited angiogenesis in endothelial cells. These results suggested that MMPP had great promise as a novel VEGFR2 inhibitor with potent anti-angiogenic properties for cancer treatment via VEGFR2/AKT/ERK/NF-κB signaling pathway.

A bivalent form of a RBD-specific synthetic antibody effectively neutralizes SARS-CoV-2 variants.

Coronavirus Disease 2019 (COVID-19) pandemic is severely impacting the world, and tremendous efforts have been made to deal with it. Despite many advances in vaccines and therapeutics, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants remains an intractable challenge. We present a bivalent Receptor Binding Domain (RBD)-specific synthetic antibody, specific for the RBD of wild-type (lineage A), developed from a non-antibody protein scaffold composed of LRR (Leucine-rich repeat) modules through phage display. We further reinforced the unique feature of the synthetic antibody by constructing a tandem dimeric form. The resulting bivalent form showed a broader neutralizing activity against the variants. The in vivo neutralizing efficacy of the bivalent synthetic antibody was confirmed using a human ACE2-expressing mouse model that significantly alleviated viral titer and lung infection. The present approach can be used to develop a synthetic antibody showing a broader neutralizing activity against a multitude of SARS-CoV-2 variants.

Association between lone work and self-rated health status: using the 5th Korean Working Conditions Survey.

Background: Lone workers are generally defined as individuals who work alone without supervision, including self-employed people. While lone workers are considered a vulnerable group in some countries, there is a lack of research on their health status in domestic studies. Globally, the number of lone workers has been increasing, and this trend has been further accelerated since the coronavirus disease 2019 (COVID-19) pandemic with the rise of remote work. Methods: The study analyzed data from 44,281 participants, excluding unpaid family workers, soldiers, and those with missing data. Lone workers were defined as individuals who reported having no colleagues with the same job at their current workplace. Self-rated health status was categorized as "good" or "poor." Results: This study found a statistically significant higher number of lone workers among women compare to men. The largest occupational category for lone workers was service and sales workers, followed by agriculture and fisheries workers. A majority of non-lone workers reported working 40 hours or less per week, while the majority of lone workers reported working 53 hours or more per week. In addition, lone workers had significantly poorer health status evaluations compared to non-lone workers (odds ratio: 1.297; 95% confidence interval: 1.165-1.444). Conclusions: Further research is needed to investigate the causal relationship between lone work and health, using data collected after the COVID-19 pandemic.

Genetically Stable and Scalable Nanoengineering of Human Primary T Cells via Cell Mechanoporation.

Effective tumor regression has been observed with chimeric antigen receptor (CAR) T cells; however, the development of an affordable, safe, and effective CAR-T cell treatment remains a challenge. One of the major obstacles is that the suboptimal genetic modification of T cells reduces their yield and antitumor activity, necessitating the development of a next-generation T cell engineering approach. In this study, we developed a nonviral T cell nanoengineering system that allows highly efficient delivery of diverse functional nanomaterials into primary human T cells in a genetically stable and scalable manner. Our platform leverages the unique cell deformation and restoration process induced by the intrinsic inertial flow in a microchannel to create nanopores in the cellular membrane for macromolecule internalization, leading to effective transfection with high scalability and viability. The proposed approach demonstrates considerable potential as a practical alternative technique for improving the current CAR-T cell manufacturing process.

Oligomeric states of ASC specks regulate inflammatory responses by inflammasome in the extracellular space.

Inflammasomes are multi-protein complexes and play a crucial role in host defense against pathogens. Downstream inflammatory responses through inflammasomes are known to be related to the oligomerization degree of ASC specks, but the detailed mechanism still remains unexplored. Here, we demonstrate that oligomerization degrees of ASC specks regulate the caspase-1 activation in the extracellular space. A protein binder specific for a pyrin domain (PYD) of ASC (ASCPYD) was developed, and structural analysis revealed that the protein binder effectively inhibits the interaction between PYDs, disassembling ASC specks into low oligomeric states. ASC specks with a low oligomerization degree were shown to enhance the activation of caspase-1 by recruiting and processing more premature caspase-1 through interactions between CARD of caspase-1 (caspase-1CARD) and CARD of ASC (ASCCARD). These findings can provide insight into controlling the inflammasome-mediated inflammatory process as well as the development of inflammasome-targeting drugs.

Epigenetic Regulations in Mammalian Cells: Roles and Profiling Techniques.

The genome is almost identical in all the cells of the body. However, the functions and morphologies of each cell are different, and the factors that determine them are the genes and proteins expressed in the cells. Over the past decades, studies on epigenetic information, such as DNA methylation, histone modifications, chromatin accessibility, and chromatin conformation have shown that these properties play a fundamental role in gene regulation. Furthermore, various diseases such as cancer have been found to be associated with epigenetic mechanisms. In this study, we summarized the biological properties of epigenetics and single-cell epigenomic profiling techniques, and discussed future challenges in the field of epigenetics.

Standards for recognition and approval rate of occupational cerebro-cardiovascular diseases in Korea.

Background: Although working hours have decreased in Korea, they are still high compared to that of other countries. In Korea, cardiovascular and cerebrovascular diseases (CCVDs) related to overwork in Korea continually occur, and the social burden from overwork is estimated to be high. This study investigated the amendment of regulations affecting the approval rate of occupational CCVDs. Methods: The change in approval rate of occupational CCVDs and related regulations were investigated using the Act and public notice on the standards for recognition of occupational CCVDs and the yearbooks of the Ministry of Employment and Labor. The CCVD mortality was estimated using data on the number of deaths according to the cause of death, the number of employed people, and resident registration population aged 15-64 years. The cumulative mortality of CCVDs was estimated using the Kaplan-Meier method. Results: Since the establishment of the standards for recognition in Korea in 1982, the scope of occupational diseases has been expanded to include intracerebral hemorrhage, subarachnoid hemorrhage, cerebral infarction, myocardial infarction, and aortic dissection. In 2013, the concept of working hours was introduced in chronic overwork. The approval rate of occupational CCVDs was 44.7% in 2006, which decreased to 12.9% in 2011. After the improvement of related regulations, the approval rate increased to 41.3% in 2018. From 2000 to 2017, the CCVD mortality of both the unemployed and employed tended to decrease, and their cumulative CCVD mortalities were 549.3 and 319.7 per 100,000 people, respectively. Conclusions: CCVDs are recognized as occupational diseases in Korea. The amendments to the standards for recognition, the introduction of the Occupational Disease Adjudication Committee, the principle of presumption, and the reduction of working hours have changed the approval rate of occupational CCVDs. A strategic approach is needed to further reduce the incidence of CCVDs.

Photobiomodulation Attenuated Cognitive Dysfunction and Neuroinflammation in a Prenatal Valproic Acid-Induced Autism Spectrum Disorder Mouse Model.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication and interaction disorders, as well as repetitive and restrictive behaviors. To date, no effective treatment strategies have been identified. However, photobiomodulation (PBM) is emerging as a promising treatment for neurological and neuropsychiatric disorders. We used mice exposed to valproic acid (VPA) as a model of ASD and found that pathological behavioral and histological changes that may have been induced by VPA were attenuated by PBM treatment. Pregnant mice that had been exposed to VPA were treated with PBM three times. Thereafter, we evaluated the offspring for developmental disorders, motor function, hyperactivity, repetitive behaviors, and cognitive impairment. PBM attenuated many of the pathological behaviors observed in the VPA-induced ASD mouse model. In addition, pathophysiological analyses confirmed that the increase in activated microglia and astrocytes observed in the VPA-induced ASD mouse model was attenuated by PBM treatment. This suggests that PBM can counteract the behavioral changes caused by neuroinflammation in ASD. Therefore, our data show that PBM has therapeutic potential and may reduce the prevalence of neurodevelopmental disorders such as ASD.

Catalytic DxD motif caged in Asx-turn and Met-aromatic interaction attenuates the pathogenic glycosylation of SseK2/NleB2 effectors.

Pathogenic bacteria encode virulent glycosyltransferases that conjugate various glycans onto host crucial proteins, which allows adhesion to mammalian cells and modulates host cellular processes for pathogenesis. Escherichia coli NleB1, Citrobacter rodentium NleB, and Salmonella enterica SseK1/3 type III effectors fatally glycosyltransfer N-acetyl glucosamine (GlcNAc) from UDP-GlcNAc to arginine residues of death domain-containing proteins that regulate host inflammation, intra-bacterial proteins, and themselves, whose post-translational modification disrupts host immune functions and prolongs bacterial viability inside host cells. However, unlike the similar NleB1/SseK1/SseK3, E. coli NleB2 and S. enterica SseK2 show deficient GlcNAcylation and neither intra-bacterial glycosylation nor auto-glycosylation. Here, as the major factor in SseK2/NleB2 deficiency, we focused on the catalytic Asp-x-Asp (DxD) motif conserved throughout all O-/N-glycosyltransferases to coordinate Mn2+. All DxD motifs in apo-glycosyltransferases form Type-I-turns for binding Mn2+, similar to the ligand-bound DxD motif, whereas TcnA/SseK2/NleB2 DxD motifs form Asx-turns, which are unable to bind Mn2+. Interestingly, methionine of the NleB2 DMD motif forms triple Met-aromatic interactions, as found in age-associated diseases and tumor necrosis factor (TNF) ligand-receptor complexes. The NleB1 A222M mutation induces triple Met-aromatic interactions to steeply attenuate glycosylation activity to 3% of that in the wild type. Thus, the characteristic conformation of the DxD motif is essential for binding Mn2+, donors, and glycosylate targets. This explains why SseK2/NleB2 effectors with the DxD motif caged in the Asp-/Asn-turn (Asx-turn) and triple Met-aromatic interactions have lower glycosyltransferase activity than that of other fatal NleB1/SseK1/SseK3 toxins.

Genomic Mutations of the STAT5 Transcription Factor Are Associated with Human Cancer and Immune Diseases.

Signal transducer and activation of transcription 5 (STAT5) is a key transcription factor that regulates various biological processes in mammalian development. Aberrant regulation of STAT5 has also been causally linked to many diseases, including cancers and immune-related diseases. Although persistent activation of STAT5 due to dysregulation of the signaling cascade has been reported to be associated with the progression of solid tumors and leukemia, various genomic mutations of STAT5 have also been found to cause a wide range of diseases. The present review comprehensively summarizes results of recent studies evaluating the intrinsic function of STAT5 and the link between STAT5 mutations and human diseases. This review also describes the types of disease models useful for investigating the mechanism underlying STAT5-driven disease progression. These findings provide basic knowledge for understanding the regulatory mechanisms of STAT5 and the progression of various diseases resulting from aberrant regulation of STAT5. Moreover, this review may provide insights needed to create optimal disease models that reflect human disease associated STAT5 mutations and to design gene therapies to correct STAT5 mutations.

Mammary-Enriched Transcription Factors Synergize to Activate the Wap Super-Enhancer for Mammary Gland Development.

Super-enhancers are large clusters of enhancers critical for cell-type-specific development. In a previous study, 440 mammary-specific super-enhancers, highly enriched for an active enhancer mark H3K27ac; a mediator MED1; and the mammary-enriched transcription factors ELF5, NFIB, STAT5A, and GR, were identified in the genome of the mammary epithelium of lactating mice. However, the triggering mechanism for mammary-specific super-enhancers and the molecular interactions between key transcription factors have not been clearly elucidated. In this study, we investigated in vivo protein-protein interactions between major transcription factors that activate mammary-specific super-enhancers. In mammary epithelial cells, ELF5 strongly interacted with NFIB while weakly interacting with STAT5A, and it showed modest interactions with MED1 and GR, a pattern unlike that in non-mammary cells. We further investigated the role of key transcription factors in the initial activation of the mammary-specific Wap super-enhancer, using CRISPR-Cas9 genome editing to introduce single or combined mutations at transcription factor binding sites in the pioneer enhancer of the Wap super-enhancer in mice. ELF5 and STAT5A played key roles in igniting Wap super-enhancer activity, but an intact transcription factor complex was required for the full function of the super-enhancer. Our study demonstrates that mammary-enriched transcription factors within a protein complex interact with different intensities and synergize to activate the Wap super-enhancer. These findings provide an important framework for understanding the regulation of cell-type-specific development.

Cohort Profile: Gachon Regional Occupational Cohort Study (GROCS).

Background/Aims: The Gachon Regional Occupational Cohort Study (GROCS) is a large-scale longitudinal study of occupational safety and health data (covering Work Environment Monitoring, Workers' Health Surveillance, and Occupational Health Service) conducted by the Gachon University Gil Medical Center (GUGMC) in Incheon, Republic of Korea. We conducted GROCS to identify the health effects of workers' occupational risks, behavior, socioeconomic status, and life style. Methods: The GROCS includes data from Work Environment Monitoring, Workers' Health Surveillance, and Occupational Health Service. The baseline year for all data collection was 2018. Work Environment Monitoring was conducted in 240 companies located in Incheon. General Health Examination and Special Health Examination were performed on 32,725 and 9,504 workers, respectively. Occupational Health Services were provided to 16,883 workers in 171 companies. These data have been collected and operated at an external data management institution and were provided as a retrospective cohort after removing personal identification information. Results: In 2018, the total number of companies was 2,854, among which which 488 special Health Examination, 171 Work Environment Monitoring, and 240 Occupational Health Service. The proportion of companies undergoing Special Health Examination was 17.1%, the proportion of companies undergoing Work Environment Monitoring was 8.4%, and the proportion of Companies undergoing Occupational Health Service was 6.0%. Conclusion: GROCS expects researchers to utilize its useful and reliable resource for occupational health and surveillance with for academic or political purposes to lead to improved workers' health and working environment.

Analysis of self-reported mental health problems among the self-employed compared with paid workers in the Republic of Korea.

Background: As self-employed workers are vulnerable to health problems, this study aimed to analyze mental health problems and sleep disturbances among self-employed workers compared with paid workers in Korea. Methods: A total of 34,750 workers (23,938 paid workers and 10,812 self-employed workers) were analyzed from the fifth Korean Working Condition Survey, which included 50,205 households collected by stratified sampling in 2017. To compare mental health problems and sleep disturbance among self-employed workers and paid workers, multivariate logistic regression analyses were performed. Results: The odds ratio in self-employed workers compared with paid workers was 1.25 (95% confidence interval [CI]: 1.09-1.42) for anxiety, 1.11 (95% CI: 1.04-1.17) for overall fatigue, 1.11 (95% CI: 1.04-1.20) for difficulty falling asleep, 1.10 (95% CI: 1.02-1.18) for difficulty maintaining sleep and 1.24 (95% CI: 1.16-1.32) for extreme fatigue after waking up. Conclusions: Self-employed workers in Korea have a higher risk of self-reported mental health problems and sleep disturbances than paid workers. Further studies with a longitudinal design and structured evaluation are required to investigate the causal relationship between health problems and self-employment.

Cohort Profile: The Korean Vietnam War Veterans' Health Study Cohort (KOVECO).

During the Vietnam War, many troops and citizen were exposed to large amounts of Agent Orange (AO), and the hazardous effects of AO are continuously being researched and reported. The Korean Vietnam War Veterans' Health Study Cohort (KOVECO) is a retrospective cohort to demonstrate the health status of the Korean Vietnam War veterans and their second-generation offsprings. The KOVECO is a collaboration of data from the Ministry of Patriots and Veterans Affairs and the National Health Insurance Sharing Service from 2002 to 2018. The study participants were all Korean Vietnam War veterans and their second-generation offsprings, and the references were the general population in which gender and region were matched with the participants. As of 2002, 191,272 Vietnam War veterans (1,000,320 comparisons) and 1,963,402 s-generations (1,173,061 references) were included in the cohort. The KOVECO consists of personal information, medical facility visit information, and general health examination information. The KOVECO could act as a health surveillance system, which would be able to detect long-term health effects caused by exposure to AO and provide a direction for policy making through academic research.

Computational design of a neutralizing antibody with picomolar binding affinity for all concerning SARS-CoV-2 variants.

Coronavirus disease 2019, caused by SARS-CoV-2, remains an on-going pandemic, partly due to the emergence of variant viruses that can "break-through" the protection of the current vaccines and neutralizing antibodies (nAbs), highlighting the needs for broadly nAbs and next-generation vaccines. We report an antibody that exhibits breadth and potency in binding the receptor-binding domain (RBD) of the virus spike glycoprotein across SARS coronaviruses. Initially, a lead antibody was computationally discovered and crystallographically validated that binds to a highly conserved surface of the RBD of wild-type SARS-CoV-2. Subsequently, through experimental affinity enhancement and computational affinity maturation, it was further developed to bind the RBD of all concerning SARS-CoV-2 variants, SARS-CoV-1 and pangolin coronavirus with pico-molar binding affinities, consistently exhibited strong neutralization activity against wild-type SARS-CoV-2 and the Alpha and Delta variants. These results identify a vulnerable target site on coronaviruses for development of pan-sarbecovirus nAbs and vaccines.

Environmental Pyrethroid Exposure and Cognitive Dysfunction in U.S. Older Adults: The NHANES 2001-2002.

Pyrethroid compounds are widely used in household insecticides and agricultural pesticides. Recent studies, however, report that pyrethroid exposures affect neurobehavioral function in animals and may be associated with adverse neurocognitive development in children. This study aimed to examine the association between pyrethroid exposure and cognitive dysfunction in older adults using a well-defined general population. We analyzed data from 336 individuals, aged 60-84 years, who participated in the National Health and Nutrition Examination Survey 2001-2002. We used urinary 3-phenoxybenzoic acid (3-PBA) concentration as a biomarker of pyrethroid exposures and assessed cognitive function with the digit-symbol coding test. The geometric means (±geometric standard errors) of creatinine-uncorrected and corrected urinary 3-PBA were 0.30 (±0.87) µg/L and 0.36 (±0.89) µg/g. After adjusting for sociodemographic factors, higher 3-PBA concentrations (> vs. ≤0.30 µg/g creatinine (median)) were associated with lower scores of cognitive function (-3.83 95% confidence interval: -7.11, -0.54). Significance was persistent after additionally adjusting for physical activity and smoking pack-year (-3.76 95% CI: -7.16, -0.36) and further adjusting for BMI and presence of hypertension and diabetes (-3.82 95% CI: -6.92, -0.71). Our findings suggest that pyrethroid exposure is associated with cognitive dysfunction in older adults.