Lamins Organize the Global Three-Dimensional Genome from the Nuclear Periphery.

Lamins are structural components of the nuclear lamina (NL) that regulate genome organization and gene expression, but the mechanism remains unclear. Using Hi-C, we show that lamins maintain proper interactions among the topologically associated chromatin domains (TADs) but not their overall architecture. Combining Hi-C with fluorescence in situ hybridization (FISH) and analyses of lamina-associated domains (LADs), we reveal that lamin loss causes expansion or detachment of specific LADs in mouse ESCs. The detached LADs disrupt 3D interactions of both LADs and interior chromatin. 4C and epigenome analyses further demonstrate that lamins maintain the active and repressive chromatin domains among different TADs. By combining these studies with transcriptome analyses, we found a significant correlation between transcription changes and the interaction changes of active and inactive chromatin domains These findings provide a foundation to further study how the nuclear periphery impacts genome organization and transcription in development and NL-associated diseases.

Rapid response of nail psoriasis to secukinumab in patients with moderate to severe psoriasis after 12 weeks of treatment with a total of 24 weeks of follow-up.

BACKGROUND/OBJECTIVES: Nail psoriasis, a subtype of psoriasis, can cause significant pain, disability, and reduced quality of life. Despite the established efficacy of anti-IL17 secukinumab in improving skin psoriasis, there is a lack of clinical trials focusing on nail psoriasis as primary endpoint. This study aims to investigate the efficacy of secukinumab in treating nail psoriasis in patients with moderate to severe psoriasis. METHODS: We prospectively recruited patients newly diagnosed with moderate to severe psoriasis in single centre from January 2021 to January 2022 who were treated with secukinumab. RESULTS: A total of 16 patients consisting of 9 males and 7 females were included. Their mean age was 38.88 ± 10.29 years. They had an average initial Nail Psoriasis Severity Index (NAPSI) score of 45.06 ± 20.39 and an average NAPSI score at 12 weeks of 8.94 ± 13.50, showing a significant (p < 0.05) decrease of NAPSI score after 12 weeks of secukinumab treatment. After 24 weeks of treatment, NAPSI score was decreased to 5.12 ± 8.52. CONCLUSION: Secukinumab rapidly improved nail psoriasis after 12 weeks of treatment, with further enhancement at 24 weeks, suggesting its potential as a potent therapeutic option for nail psoriasis.

Anatomical study of the sacrotuberous ligament and the hamstring muscles: A histomorphological analysis.

The sacrotuberous ligament (STL) and the hamstrings are important structures that are mutually connected and influenced by the pelvis. However, the anatomical connectivity and histological characteristics of these structures remain unclear. The present study aimed to comprehensively investigate the relationship between the STL and the proximal hamstrings through histological analysis. Sixteen specimens were obtained from eight fresh cadavers (mean age at death, 73.4 years). Verhoeff Van Gieson, Masson's trichrome, and immunohistochemical staining were used to analyze the connectivity between the STL and the hamstrings and to verify the ratios of collagen and elastic fibers. Dense connective tissue that overlapped tightly between the STL and hamstrings was observed. The relative ratios of collagen and elastic fibers between the STL and hamstrings characteristically identified regional differences. The ratio of elastic fibers to collagen in the biceps femoris (BF) was ~38.6 ± 4.7%, and the lowest ratio was 5.9 ± 2.6% observed in the semimembranosus (SM). In the case of the BF, contractibility is well-regulated due to a high content of elastic fibers; however, the muscular structure of the BF is relatively fragile due to the low content of collagen. In the SM, collagen content is higher than that in the STL. This ratio of elastic fibers in the collagen analysis could provide crucial information for understanding the differences in hamstring contractility and maintaining the morphology of these structures.

Development of a Convenient and Quantitative Method for Evaluating Photosensitizing Activity Using Thiazolyl Blue Formazan Dye.

Photosensitizers cause oxidative damages in various biological systems under light. In this study, the method for analyzing photosensitizing activity of various dietary and medicinal sources was developed using 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (thiazolyl blue formazan; MTT-F) as a probe. Significant and quantitative decolorization of MTT-F was observed in the presence of photosensitizers used in this study under light but not under dark conditions. The decolorization of MTT-F occurred irradiation time-, light intensity-, and photosensitizer concentration-dependently. The decolorized MTT-F was reversibly reduced by living cells; the LC-MS/MS results indicated the formation of oxidized products with -1 m/z of base peak from MTT-F, suggesting that MTT-F decolorized by photosensitizers was its corresponding tetrazolium. The present results indicate that MTT-F is a reliable probe for the quantitative analysis of photosensitizing activities, and the MTT-F-based method can be an useful tool for screening and evaluating photosensitizing properties of various compounds used in many industrial purposes.

Age-friendly environment, social support, sense of community, and loneliness among middle-aged and older adults in Korea.

OBJECTIVES: The purpose of this research is to explore the relationship between age-friendly environment, social support, sense of community, and loneliness of Korean adults aged 45 and above. METHODS: A total of 590 participants from a cross-sectional and secondary data from an age integration survey conducted in 2018 was used for analysis. Structural equation modelling and bootstrapping method were applied to examine the mediating role of social support and sense of community on the relationship between age-friendly environment and loneliness. RESULTS: Age-friendly environment was positively associated with social support (ß=.310, p<.001) and sense of community (ß=.479, p<.001). Social support was negatively associated with loneliness (ß=-.190, p<.001). Full mediation effect of social support was observed in the pathway from age-friendly environment to loneliness (95% CI: -0.135 to -0.036). CONCLUSION: Social support was fundamental in lowering loneliness in an age-friendly environment. There was no significant association linking age-friendly environment, sense of community, and loneliness. The results support the adoption of AFE to protect people at risk of loneliness with social support mediating this relationship.

Challenges and Future Trends in the Treatment of Psoriasis.

Psoriasis is a chronic inflammatory skin disorder, and current treatments include topical therapies, phototherapy, systemic immune modulators, and biologics, aiming to alleviate symptoms and improve quality of life. However, challenges persist, such as adverse effects, treatment resistance, high costs, and variability in response among individuals. The future of psoriasis treatment shows promising emerging trends. New biologic agents targeting novel pathways, such as interleukin 23 inhibitors like mirikizumab, offer enhanced efficacy. Small molecule inhibitors like RORγt inhibitors and ROCK2 inhibitors provide additional treatment options. Combination therapies, including biologics with methotrexate, may improve treatment response. Advancements in topical treatments utilizing microneedles and nanoparticle-based carriers can enhance drug delivery and improve therapeutic outcomes. Biomarkers and multi-omics technologies hold potential for personalized treatment approaches, thus aiding in diagnosis, predicting treatment response, and guiding therapeutic decisions. Collaboration among researchers, clinicians, and industry stakeholders is crucial to translating these scientific breakthroughs into clinical practice. By addressing current challenges and exploring these promising trends, we can optimize psoriasis management and improve the lives of those affected by this chronic condition.

Smoking and Periodontitis Can Play a Synergistic Role in the Development of Psoriasis: A Nationwide Cohort Study.

BACKGROUND: Periodontitis is a chronic inflammatory disorder involving the periodontium. The precise nature of the association between periodontitis and psoriasis has not been determined. OBJECTIVE: This nationwide population-based study investigated the relationship between periodontitis and the risk of psoriasis. METHODS: A health screening database, which is a sub-dataset of the Korean National Health Insurance System database, was used in this study. Subjects with (n = 1,063,004) and without (n = 8,655,587) periodontitis who underwent health examinations from January to December 2009 were followed for 9 years. RESULTS: In multivariable analysis, compared to the non-periodontitis group, periodontitis patients had a significantly higher risk of developing psoriasis (hazard ratio 1.116, 95% confidence interval 1.101-1.13). Non-smokers with periodontitis had an 11% increase in risk of psoriasis and smokers with periodontitis had a 26.5% increase in risk of psoriasis compared to non-smokers without periodontitis. CONCLUSION: Our study highlights periodontitis as a potential independent risk factor for psoriasis, increasing awareness of the synergistic role of smoking and periodontitis in the pathogenesis of psoriasis.

Occult Blood in Feces Is Associated with Increased Risk of Psoriasis.

BACKGROUND: The fecal immunochemistry test (FIT) has been proposed as a surrogate marker of intestinal inflammation. Psoriasis is a chronic inflammatory skin disease that is linked to underlying systemic inflammatory conditions, including inflammatory bowel disease. METHODS: We investigated the association between occult blood in feces and the risk of psoriasis using data from the National Health Insurance System. This study was conducted involving 1,395,147 individuals who underwent health examinations from January 2009 to December 2012 and were followed up until the end of 2017. RESULTS: The incidence of psoriasis (per 1,000 person-years) was 3.76 versus 4.14 (FIT-negative versus FIT-positive group) during a median follow-up of 6.68 years. In the multivariable-adjusted model, the hazard ratios for psoriasis were 1.03 for one positive FIT result, 1.12 for two positive FIT results, and 1.34 for three positive FIT results compared with negative FIT results. CONCLUSION: The risk of psoriasis was significantly increased in patients with positive FIT results compared to the FIT-negative population.

The FMRP-MOV10 complex: a translational regulatory switch modulated by G-Quadruplexes.

The Fragile X Mental Retardation Protein (FMRP) is an RNA binding protein that regulates translation and is required for normal cognition. FMRP upregulates and downregulates the activity of microRNA (miRNA)-mediated silencing in the 3' UTR of a subset of mRNAs through its interaction with RNA helicase Moloney leukemia virus 10 (MOV10). This bi-functional role is modulated through RNA secondary structures known as G-Quadruplexes. We elucidated the mechanism of FMRP's role in suppressing Argonaute (AGO) family members' association with mRNAs by mapping the interacting domains of FMRP, MOV10 and AGO and then showed that the RGG box of FMRP protects a subset of co-bound mRNAs from AGO association. The N-terminus of MOV10 is required for this protection: its over-expression leads to increased levels of the endogenous proteins encoded by this co-bound subset of mRNAs. The N-terminus of MOV10 also leads to increased RGG box-dependent binding to the SC1 RNA G-Quadruplex and is required for outgrowth of neurites. Lastly, we showed that FMRP has a global role in miRNA-mediated translational regulation by recruiting AGO2 to a large subset of RNAs in mouse brain.

Skin Barrier Function and the Microbiome.

Human skin is the largest organ and serves as the first line of defense against environmental factors. The human microbiota is defined as the total microbial community that coexists in the human body, while the microbiome refers to the collective genome of these microorganisms. Skin microbes do not simply reside on the skin but interact with the skin in a variety of ways, significantly affecting the skin barrier function. Here, we discuss recent insights into the symbiotic relationships between the microbiome and the skin barrier in physical, chemical, and innate/adaptive immunological ways. We discuss the gut-skin axis that affects skin barrier function. Finally, we examine the effects of microbiome dysbiosis on skin barrier function and the role of these effects in inflammatory skin diseases, such as acne, atopic dermatitis, and psoriasis. Microbiome cosmetics can help restore skin barrier function and improve these diseases.

Interfering with Color Response by Porphyrin-Related Compounds in the MTT Tetrazolium-Based Colorimetric Assay.

Porphyrin compounds are widely distributed in various natural products and biological systems. In this study, effects of porphyrin-related compounds including zinc protoporphyrin (ZnPP), protoporphyrin IX (PPIX), cyanocobalamin (CBL), hemin, and zinc phthalocyanine (ZnPC) were analyzed on color response of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tetrazolium-based assay, a commonly-used method for analyzing cell viability. Color responses of MTT formazan formed in cells treated with ZnPP, PPIX, or ZnPC were significantly reduced even at submicromolar concentrations without affecting cell viability, whereas hemin and CBL did not. ZnPP, PPIX, and ZnPC rapidly induced degradation of MTT formazan already-produced by cells when exposed to light, but not under a dark condition. Photosensitizing properties of the three compounds were also verified through extensive generation of reactive oxygen species under light. The porphyrins did not affect the stability of water-soluble formazans including XTT, WST-1, WST-8, and MTS formazans. Several factors including different light sources and antioxidants modulated the degradation process of MTT formazan by the porphyrins. The results suggest that certain porphyrin compounds could cause a severe artifact in the MTT assay through rapid degradation of formazan dye due to their photosensitizing property, which needs to be considered carefully in the related assays.

Herpes Zoster and Subsequent Cancer Risk: A Nationwide Population-Based Cohort Study in Korea.

BACKGROUND: It is well known that an immunosuppressed status such as cancer is a risk factor for herpes zoster (HZ), but little is known about whether HZ affects cancer development. OBJECTIVES: This study aimed to investigate the association between HZ and subsequent cancer risk by cancer type. METHODS: We conducted a nationwide retrospective cohort study using the Korean National Health Insurance claims database. The study enrolled 1,568,818 patients: 784,409 diagnosed with HZ between 2010 and 2015 were included in the HZ group, and 784,409 matched controls without HZ were included in the non-HZ group, with 1:1 exact matching for age, sex, and index year. Hazard ratios (HRs) were calculated for the risk of cancers based on anatomical site according to the HZ status using the Cox proportional hazards regression models. RESULTS: During a mean follow-up period of 6 years, 22,235 and 22,316 patients in the HZ group and the non-HZ group, respectively, developed cancer (incidence rate: 7.6 vs. 7.7 per 1,000 person-years). After adjusting for age, sex, and comorbidities, the overall risk of cancers was slightly decreased in the HZ group compared with the non-HZ group (HR, 0.999; 95% confidence interval [CI], 0.98-1.02). In post hoc analyses on organ site, the HZ group had significantly increased risk of hematologic malignancies, including multiple myeloma (HR, 1.63; 95% CI, 1.37-1.95), leukemia (HR, 1.20; 95% CI, 1.03-1.39), and lymphoma (HR, 1.15; 95% CI, 1.02-1.30) compared with the non-HZ group. Conversely, the risk of cancers in the liver (HR, 0.87; 95% CI, 0.82-0.93) and larynx (HR, 0.73; 95% CI, 0.58-0.92) were significantly decreased in the HZ group compared with the non-HZ group. CONCLUSIONS: Although the risk of developing some hematological cancers increased in patients with HZ, solid cancers including liver and laryngeal cancers showed a negative association with HZ.

Age-friendly environments and depressive symptoms among Korean adults: The mediating effects of loneliness.

OBJECTIVES: In this study, we examined (1) group differences with regard to age-friendly environments (AFE), loneliness, and depressive symptoms among younger, middle-aged, and older Korean adults; (2) the relationship of AFE to loneliness and depressive symptoms; and (3) the mediating effect of loneliness on the relationship between AFE and depressive symptoms among three Korean adult groups. METHOD: We used a cross-sectional survey design featuring multistage quota sampling. Study participants were 1,017 Korean adults aged 18 years or older. Multi-group structural equation modeling was used for data analysis. RESULTS: Statistically significant age group differences were found in the mean values of loneliness and depressive symptoms, but no significant age group differences in the mean values of AFE were observed. Older adults showed a significant relationship between AFE and loneliness, while their younger counterparts demonstrated a significant relationship between AFE and depressive symptoms. The mediating effect of loneliness on the association between AFE and depressive symptoms was found only for the older age group. CONCLUSION: The results of the study contribute to the existing understanding of AFE and mental health among Korean adults, while providing service providers and policy makers with fundamental background information on alleviating depression.

Angiogenesis in Chronic Inflammatory Skin Disorders.

Angiogenesis, the growth of new blood vessels from preexisting vessels, is associated with inflammation in various pathological conditions. Well-known angiogenetic factors include vascular endothelial growth factor (VEGF), angiopoietins, platelet-derived growth factor, transforming growth factor-ß, and basic fibroblast growth factor. Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) have recently been added to an important angiogenic factor. Accumulating evidence indicates associations between angiogenesis and chronic inflammatory skin diseases. Angiogenesis is deeply involved in the pathogenesis of psoriasis. VEGF, angiopoietins, tumor necrosis factor-a, interleukin-8, and interleukin-17 are unregulated in psoriasis and induce angiogenesis. Angiogenesis may be involved in the pathogenesis of atopic dermatitis, and in particular, mast cells are a major source of VEGF expression. Angiogenesis is an essential process in rosacea, which is induced by LL-37 from a signal cascade by microorganisms, VEGF, and MMP-3 from mast cells. In addition, angiogenesis by increased VEGF has been reported in chronic urticaria and hidradenitis suppurativa. The finding that VEGF is expressed in inflammatory skin lesions indicates that inhibition of angiogenesis is a useful strategy for treatment of chronic, inflammatory skin disorders.

Structural and Functional Changes and Possible Molecular Mechanisms in Aged Skin.

Skin aging is a complex process influenced by intrinsic and extrinsic factors. Together, these factors affect the structure and function of the epidermis and dermis. Histologically, aging skin typically shows epidermal atrophy due to decreased cell numbers. The dermis of aged skin shows decreased numbers of mast cells and fibroblasts. Fibroblast senescence contributes to skin aging by secreting a senescence-associated secretory phenotype, which decreases proliferation by impairing the release of essential growth factors and enhancing degradation of the extracellular matrix through activation of matrix metalloproteinases (MMPs). Several molecular mechanisms affect skin aging including telomere shortening, oxidative stress and MMP, cytokines, autophagic control, microRNAs, and the microbiome. Accumulating evidence on the molecular mechanisms of skin aging has provided clinicians with a wide range of therapeutic targets for treating aging skin.

Inhibition of Hippo Signaling Improves Skin Lesions in a Rosacea-Like Mouse Model.

The Hippo signaling pathway plays a key role in regulating organ size and tissue homeostasis. Hippo and two of its main effectors, yes-associated protein (YAP) and WWTR1 (WW domain-containing transcription regulator 1, commonly listed as TAZ), play critical roles in angiogenesis. This study investigated the role of the Hippo signaling pathway in the pathogenesis of rosacea. We performed immunohistochemical analyses to compare the expression levels of YAP and TAZ between rosacea skin and normal skin in humans. Furthermore, we used a rosacea-like BALB/c mouse model induced by LL-37 injections to determine the roles of YAP and TAZ in rosacea in vivo. We found that the expression levels of YAP and TAZ were upregulated in patients with rosacea. In the rosacea-like mouse model, we observed that the clinical features of rosacea, including telangiectasia and erythema, improved after the injection of a YAP/TAZ inhibitor. Additionally, treatment with a YAP/TAZ inhibitor reduced the expression levels of YAP and TAZ and diminished vascular endothelial growth factor (VEGF) immunoreactivity in the rosacea-like mouse model. Our findings suggest that YAP/TAZ inhibitors can attenuate angiogenesis associated with the pathogenesis of rosacea and that both YAP and TAZ are potential therapeutic targets for patients with rosacea.

Safety and efficacy evaluations of an adeno-associated virus variant for preparing IL10-secreting human neural stem cell-based therapeutics.

Gene therapy technologies are inevitably required to boost the therapeutic performance of cell therapies; thus, validating the efficacy of gene carriers specifically used for preparing cellular therapeutics is a prerequisite for evaluating the therapeutic capabilities of gene and cell combinatorial therapies. Herein, the efficacy of a recombinant adeno-associated virus derivative (rAAVr3.45) was examined to evaluate its potential as a gene carrier for genetically manipulating interleukin-10 (IL10)-secreting human neural stem cells (hNSCs) that can potentially treat ischemic injuries or neurological disorders. Safety issues that could arise during the virus preparation or viral infection were investigated; no replication-competent AAVs were detected in the final cell suspensions, transgene expression was mostly transient, and no severe interference on endogenous gene expression by viral infection occurred. IL10 secretion from hNSCs infected by rAAVr3.45 encoding IL10 did not alter the transcriptional profile of any gene by more than threefold, but the exogenously boosted IL10 was sufficient to provoke immunomodulatory effects in an ischemic brain injury animal model, thereby accelerating the recovery of neurological deficits and the reduction of brain infarction volume. This study presents evidence that rAAVr3.45 can be potentially used as a gene carrier to prepare stem cell therapeutics.

Prevalence and clinicopathologic characteristics of multiple myeloma with cutaneous involvement: A case series from Korea.

BACKGROUND: Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the presence of a clonal proliferation of tumor cells. Cutaneous involvement of MM is very rare and remains poorly understood. OBJECTIVE: The aim of this study was to examine the clinical and histopathologic characteristics of cutaneous involvement in MM and identify factors associated with overall survival of MM with cutaneous involvement. METHODS: The medical records of 1228 patients with MM were retrieved and analyzed. Of those patients, 14 with cutaneous involvement of MM (1.14%) were further evaluated for their clinical and histopathologic findings. RESULTS: Patients with cutaneous involvement showed significantly reduced overall survival compared with those without cutaneous involvement (median, 28 vs. 57 months; hazard ratio, 1.929; 95% confidence interval, 1.030-3.613). In subgroup analyses of patients with MM with cutaneous involvement, erythematous nodules (P = .004), multiple cutaneous lesions (P = .002), and absence of a grenz zone (P = .004) were clinicopathologic features associated with reduced overall survival after Bonferroni correction. LIMITATIONS: The retrospective design and the small sample size are the limitations. CONCLUSION: Cutaneous involvement accounted for about 1.14% of patients with MM and was associated with reduced overall survival.

Long-pulsed 1064-nm Nd: YAG laser ameliorates LL-37-induced rosacea-like skin lesions through promoting collagen remodeling in BALB/c mice.

Long-pulsed 1064-nm neodymium: yttrium-aluminum-garnet laser (LPND) effectively treats rosacea, although the underlying mechanism is unclear, to evaluate the histological effects and molecular mechanism of LPND on LL-37-induced rosacea-like skin lesions in mice. Intradermal injection of LL-37 was performed into the dorsal skin of BALB/c mice (n = 30) twice a day for 2 days. Fifteen mice were treated with LPND. After 48 h, the excised skin sample was stained for histology and type I collagen; transforming growth factor (TGF)-ß, matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase (TIMP)-1, tumor necrosis factor (TNF)-α, and interleukin (IL)-1α mRNA levels were determined by real-time RT-PCR. Intradermal injection of LL-37 induced rosacea-like clinical features. LPND treatment significantly reduced erythema and increased dermal collagen production. Levels of Type I collagen, TGF-ß, and MMP-1 mRNA were significantly higher in LPND-treated mice than in untreated mice. LPND may improve rosacea by ameliorating dermal connective tissue disorganization and elastosis through MMP-mediated dermal collagen remodeling.