Characterization of the collagen network of human cheek skin using ultrasonic microscopy.

Dermal collagen is the most abundant component of human skin and has a network structure that regulates the mechanical properties of the skin. Therefore, non-invasive characterization of the collagen network would be beneficial for the evaluation of skin conditions. The microscopic substructures of the network, which are individual bundles and fibers, have been optically investigated. However, the macroscopic structure of the collagen network has not been assessed. To evaluate the dermal collagen network, we developed two new indicators, volume filling factor (VFF) and collagen fiber texture (CFT), to analyze three-dimensional echo intensity maps of high-frequency ultrasonic microscopy. By identifying the difference in the elastic modulus components of the dermal layer of facial skin, the density and texture of the collagen network were characterized using VFF and CFT, respectively. These new indicators revealed that the density decreased and the texture became fine with facial age. This study demonstrates that ultrasonic microscopy is useful for investigating skin conditions, paving the way for diagnostic applications in dermatology and aesthetic medicine.

Characteristics of dermal vascularity in melasma and solar lentigo.

BACKGROUND /PURPOSE: Melasma and solar lentigo (SL) are major benign hyperpigmented lesions, and both have been shown to involve the dermal vasculature. This review discusses current knowledge regarding the clinical characteristics of dermal vascularity in melasma and SL, as well as the results of relevant molecular biological investigations. METHODS: PubMed and Google Scholar were searched in December 2023 to identify articles related to melasma, SL, and the dermal vasculature in these lesions. RESULTS: Vascular morphologies in melasma and SL have been detected by histological and non-invasive methods, including modalities such as optical coherence tomography. Biological studies have indicated that factors secreted from vascular endothelial cells, such as stem cell factor and endothelin-1, can promote melanogenesis. With respect to phototherapy, blood vessel-targeting laser treatments are expected to provide long-term suppression of pigmentation, but this regimen is only effective when dilated capillaries are visible. CONCLUSION: In both melasma and SL, clinical and experimental investigations are revealing the contributions of dermal vascularity to hyperpigmentation. More effective treatment may require identification of hyperpigmentation subtypes. In the future, knowledge of treatment (including phototherapy) is expected to accumulate through reliable and validated non-invasive measurements.

High IL2RA/CD25 expression is a prognostic stem cell biomarker for pediatric acute myeloid leukemia without a core-binding factor.

CD25 is an aberrant marker expressed on the leukemic stem cell (LSC) surface and an immunotherapy target in acute myeloid leukemia (AML). However, the clinical prevalence and significance of CD25 expression in pediatric AML are unknown. High IL2RA/CD25 expression in pediatric AML showed a stem cell-like phenotype, and elevated CD25 expression was associated with lower overall survival (p < .001) and event-free survival (p < .001) in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. This finding was reproduced in AML without a core-binding factor in the Children's Oncology Group study cohort. High CD25 expression has prognostic significance in pediatric AML.

Correlation between the efficacy of picosecond-domain laser treatment for solar lentigo and the vascularity in the upper dermis using optical coherence tomography angiography in Asian women.

OBJECTIVES: The purpose of this study was to noninvasively confirm the characteristics of the dermal vasculature in patients with solar lentigo (SL) and determine any association with the efficacy of picosecond-domain laser (PSL) treatment. METHODS: Thirteen facial SL lesions in 11 Asian female patients were included in this study and evaluated over 12 weeks. An Nd:YAG laser was used at 532 nm and 750 ps. Skin color and morphological structure were evaluated by ANTERA-3D® and optical coherence tomography (OCT), respectively. To analyze the vascularity in the upper dermis, an OCT angiography (OCTA) algorithm was applied to the OCT data. RESULTS: After PSL treatment, significant improvement in both hyperpigmentation and abnormally thickened epidermis was observed, but the efficacy varied for each lesion. There was a significant correlation between the change in the melanin index due to PSL treatment and preoperative vascular density in the upper dermis. CONCLUSIONS: To the best of our knowledge, this is the first report to demonstrate a correlation between the efficacy of PSL treatment of SL lesions and the vascularity in the upper dermis. Methods to evaluate the vasculature in the upper dermis may be useful for preoperative prediction of the efficacy of PSL treatment for SL lesions.

Relationship between arthritis of the second and third tarsometatarsal joints and incongruity of the first tarsometatarsal joint in patients with hallux valgus.

OBJECTIVES: Hallux valgus is associated with tarsometatarsal arthritis; its pathophysiology remains unknown. Therefore, we aimed to elucidate the relationship between arthritis of the second and third tarsometatarsal joints and incongruity of the first tarsometatarsal joint in the sagittal plane. METHODS: Forty-three patients (64 feet) with hallux valgus who underwent surgery at University Hospital Kyoto Prefectural University of Medicine were included and divided into two groups: control (without second and third tarsometatarsal joint degeneration) and osteoarthritis (with second and third tarsometatarsal joint degeneration). Intergroup comparisons of the incongruity of the first tarsometatarsal joint in the sagittal plane, age, body mass index, hallux valgus angle, first-second intermetatarsal angle, metatarsus adductus angle, Meary's angle, and calcaneal pitch angle were performed. RESULTS: The proportion of patients with incongruity of the first tarsometatarsal joint was significantly higher in the osteoarthritis group than in the control group. Logistic regression analysis identified incongruity of the first tarsometatarsal joint and metatarsus adductus angle as significant related factors for arthritis of the second and third tarsometatarsal joints. CONCLUSIONS: Incongruity of the first tarsometatarsal joint in the sagittal plane was involved in the development of arthritis of the second and third tarsometatarsal joints in patients with hallux valgus.

Interleukin-13 Mediates Non-Steroidal Anti-Inflammatory-Drug-Induced Small Intestinal Mucosal Injury with Ulceration.

Non-steroidal anti-inflammatory drugs (NSAIDs), which are antipyretics and analgesics, cause gastrointestinal disorders, such as inflammation and ulcers. To prescribe NSAIDs more safely, it is important to clarify the mechanism of NSAID-induced gastrointestinal mucosal injury. However, there is a paucity of studies on small intestinal mucosal damage by NSAIDs, and it is currently unknown whether inflammation and ulceration also occur in the small intestine, and whether mediators are involved in the mechanism of injury. Therefore, in this study, we created an animal model in which small intestinal mucosal injury was induced using NSAIDs (indomethacin; IDM). Focusing on the dynamics of immune regulatory factors related to the injury, we aimed to elucidate the pathophysiological mechanism involved. We analyzed the pathological changes in the small intestine, the expression of immunoregulatory factors (cytokines), and identified cytokine secretion and expression cells from isolated lamina propria mononuclear cells (LPMCs). Ulcers were formed in the small intestine by administering IDM. Although the mRNA expression levels of IL-1ß, IL-6, and TNFα were decreased on day 7 after IDM administration, IL-13 mRNA levels increased from day 3 after IDM administration and remained high even on day 7. The IL-13 mRNA expression and the secretion of IL-13 were increased in small intestinal LPMCs isolated from the IDM-treated group. In addition, we confirmed that IL-13 was expressed in CD4-positive T cells. These results provided new evidence that IL-13 production from CD4-positive T cells in the lamina propria of the small intestine contributes to NSAID-induced mucosal injury.

Microrheology near jamming.

The jamming transition is a nonequilibrium critical phenomenon, which governs characteristic mechanical properties of jammed soft materials, such as pastes, emulsions, and granular matters. Both experiments and theory of jammed soft materials have revealed that the complex modulus measured by conventional macrorheology exhibits a characteristic frequency dependence. Microrheology is a new type of method to obtain the complex modulus, which transforms the microscopic motion of probes to the complex modulus through the generalized Stokes relation (GSR). Although microrheology has been applied to jammed soft materials, its theoretical understanding is limited. In particular, the validity of the GSR near the jamming transition is far from obvious since there is a diverging length scale lc, which characterizes the heterogeneous response of jammed particles. Here, we study the microrheology of jammed particles by theory and numerical simulation. First, we develop a linear response formalism to calculate the response function of the probe particle, which is transformed to the complex modulus via the GSR. Then, we apply our formalism to a numerical model of jammed particles and find that the storage and loss modulus follow characteristic scaling laws near the jamming transition. Importantly, the observed scaling law coincides with that in macrorheology, which indicates that the GSR holds even near the jamming transition. We rationalize this equivalence by asymptotic analysis of the obtained formalism and numerical analysis on the displacement field of jammed particles under a local perturbation.

TP53 and RB1 alterations characterize poor prognostic subgroups in pediatric acute myeloid leukemia.

Pediatric acute myeloid leukemia (AML) is a poor prognostic subtype of pediatric leukemia. However, the detailed characteristics of many genetic abnormalities are yet to be established in this disease. Although TP53 and RB1 are established as representative tumor suppressor genes in various cancers, alterations of these two genes, especially RB1, have not been characterized in pediatric AML. We performed next-generation sequencing in 328 pediatric AML patients from the Japanese AML-05 trial to ascertain TP53 and RB1 alterations, and their prognostic implications. We identified seven patients with TP53 alterations (2.1%) and six patients with RB1 alterations (1.8%). These alterations were found in only patients without RUNX1::RUNX1T1, CBFB::MYH11, or KMT2A rearrangements. TP53 and RB1 were frequently co-deleted with their neighboring genes PRPF8 and ELF1, respectively. Patients with TP53 alterations had significantly lower 5-year overall survival (OS; 14.3% vs. 71.4%, p < 0.001) and lower 5-year event-free survival (EFS; 0% vs. 56.3%, p < 0.001); similarly, patients with RB1 had significantly lower 5-year OS (0% vs. 71.8%, p < 0.001) and lower 5-year EFS (0% vs. 56.0%, p < 0.001) when compared to patients without these alterations. In gene expression analyses, oxidative phosphorylation, glycolysis, and protein secretion were upregulated in patients with TP53 and/or RB1 alterations. Additionally, Kaplan-Meier analysis revealed that high expressions of SLC2A5, KCNAB2, and CD300LF were related to poor OS of non-core-binding factor AML patients (p < 0.001, p = 0.001, and p = 0.021, respectively). This study will contribute to the development of risk-stratified therapy and precision medicine in pediatric AML.

A Comparison of the Corneal Thickness Following Descemet's Stripping Automated Endothelial Keratoplasty and Descemet's Membrane Endothelial Keratoplasty.

PURPOSE: To compare the central corneal thickness before and after Descemet's stripping automated endothelial keratoplasty (DSAEK) and Descemet's membrane endothelial keratoplasty (DMEK), and to evaluate the recipient corneal thickness following DSAEK. METHODS: The corneal thickness was compared between two groups of eyes following DMEK and DSAEK, performed by a single surgeon between 2015 and 2017. We evaluated the recipient corneal thickness and central corneal thickness pre- and postoperatively at 1, 3, and 6 months using anterior segment optical coherence tomography. Recipient corneal thickness was defined as the corneal thickness without graft thickness. RESULTS: We included DMEK and DSAEK eyes (n = 26 each), which were similar in terms of their etiologies. Preoperatively, there was no significant difference in the central corneal thickness between the groups (DSAEK, median [interquartile range]: 721 [606.5 to 847.8] µm; and DMEK: 690 [618 to 722.3] µm; p = 0.30). Despite the tendency of the central corneal thickness to be significantly greater (p < .01) at 6 months following DSAEK (619.5 [607.8 to 661.3] µm) compared with that following DMEK (497.5 [475.8 to 525.3] µm), there was no significant difference at 6 months between the recipient corneal thickness following DSAEK (488.5 [443.8 to 515] µm) and central corneal thickness following DMEK (p = 0.54). CONCLUSIONS: DSAEK eyes display a similar tendency of stromal thinning as DMEK eyes.

UBTF-internal tandem duplication as a novel poor prognostic factor in pediatric acute myeloid leukemia.

The prognosis of pediatric acute myeloid leukemia (AML) has improved via stratification therapy. However, relapse or death occurs in 30%-40% of cases. Novel genetic factors for pediatric AML need to be elucidated to improve prognosis. We detected recurrent internal tandem duplication in upstream binding transcription factor (UBTF-ITD) in 1.2% (6/503) of Japanese pediatric patients with de novo AML. No UBTF-ITD was detected in 175 adult patients with AML or in 65 cell lines that included 15 AML, 39 acute lymphoblastic leukemia, five chronic myeloid leukemia, and six neuroblastoma cell lines. All UBTF-ITDs were found in exon 13 and shared a duplicated region. UBTF-ITD was more frequently detected in patients with trisomy 8, FLT3-ITD, WT1 mutation, and/or high PRDM16 expression (trisomy 8, 3/6; FLT3-ITD, 5/6; WT1 mutation, 2/6; and high PRDM16 expression, 6/6). Gene expression patterns of patients with UBTF-ITD were similar to those of patients with NUP98::NSD1 or FUS::ERG. Survival analysis of the AML-05 cohort revealed that patients with UBTF-ITD had worse outcomes than those without UBTF-ITD (3-year event-free survival, 20% vs. 55%; 3-year overall survival, 40% vs. 74%). Moreover, among the 27 patients with trisomy 8, all three patients with UBTF -ITD had a poor prognosis resulting in early events (relapse or non-complete remission) within 1 year. Our findings suggest that UBTF-ITD may be a novel and significant prognostic factor for pediatric patients with AML.

Low-frequency vibrational states in ideal glasses with random pinning.

Glasses exhibit spatially localized vibrations in the low-frequency regime. These localized modes emerge below the boson peak frequency ω_{BP}, and their vibrational densities of state follow g(ω)∝ω^{4} (ω is frequency). Here, we attempt to address how the localized vibrations behave through the ideal glass transition. To do this, we employ a random pinning method, which enables us to study the thermodynamic glass transition. We find that the localized vibrations survive even in equilibrium glass states. Remarkably, the localized vibrations still maintain the properties of appearance below ω_{BP} and g(ω)∝ω^{4}. Our results provide important insight into the material properties of ideal glasses.

Gap junctional intercellular communication attenuates osteoclastogenesis induced by activated osteoblasts.

Osteoblasts participate in both bone formation through the synthesis of extracellular matrix and osteoclast differentiation through the expression of osteoclast differentiation factor. Osteoblasts communicate with each other via gap junctions (GJ), which enable small molecules, such as cAMP, to move to adjacent cells. Therefore, we focused on the role of cAMP propagation between osteoblasts via GJ in the osteoclast-supporting activity of osteoblasts. Osteoclast-supporting activity was evaluated by a co-culture system of osteoblasts with bone marrow-derived mononuclear cells. In this system, ablation of Gja1, a gene encoding connexin 43, in osteoblasts promoted osteoclastogenesis induced by prostaglandin E2 (PGE2). A phosphodiesterase 4 inhibitor increased both osteoclastogenesis and the intracellular cAMP concentration ([cAMP]i) in osteoblasts. Individual cell analysis of [cAMP]i in osteoblasts revealed different responses of each osteoblast to PGE2. Moreover, measurement of real-time [cAMP]i demonstrated cAMP movement from cell to cell via GJ. The inhibition of GJ resulted in the upregulation of [cAMP]i in osteoblasts stimulated by PGE2. This study suggested that GJ intercellular communication exerts protective effects against excess osteoclastogenesis via cAMP movement between osteoblasts.

Genome-wide DNA methylation analysis in pediatric acute myeloid leukemia.

We investigated genome-wide DNA methylation patterns in 64 pediatric patients with acute myeloid leukemia (AML). Based on unsupervised clustering with the 567 most variably methylated cytosine guanine dinucleotide (CpG) sites, patients were categorized into 4 clusters associated with genetic alterations. Clusters 1 and 3 were characterized by the presence of known favorable prognostic factors, such as RUNX1-RUNX1T1 fusion and KMT2A rearrangement with low MECOM expression, and biallelic CEBPA mutations (all 8 patients), respectively. Clusters 2 and 4 comprised patients exhibiting molecular features associated with adverse outcomes, namely internal tandem duplication of FLT3 (FLT3-ITD), partial tandem duplication of KMT2A, and high PRDM16 expression. Depending on the methylation values of the 1243 CpG sites that were significantly different between FLT3-ITD+ and FLT3-ITD- AML, patients were categorized into 3 clusters: A, B, and C. The STAT5-binding motif was most frequently found close to the 1243 CpG sites. All 8 patients with FLT3-ITD in cluster A harbored high PRDM16 expression and experienced adverse events, whereas only 1 of 7 patients with FLT3-ITD in the other clusters experienced adverse events. PRDM16 expression levels were also related to DNA methylation patterns, which were drastically changed at the cutoff value of PRDM16/ABL1 = 0.10. The assay for transposase-accessible chromatin sequencing of AMLs supported enhanced chromatin accessibility around genomic regions, such as HOXB cluster genes, SCHIP1, and PRDM16, which were associated with DNA methylation changes in AMLs with FLT3-ITD and high PRDM16 expression. Our results suggest that DNA methylation levels at specific CpG sites are useful to support genetic alterations and gene expression patterns of patients with pediatric AML.

Clinical significance of RAS pathway alterations in pediatric acute myeloid leukemia.

RAS pathway alterations have been implicated in the pathogenesis of various hematological malignancies. However, their clinical relevance in pediatric acute myeloid leukemia (AML) is not well characterized. We analyzed the frequency, clinical significance, and prognostic relevance of RAS pathway alterations in 328 pediatric patients with de novo AML. RAS pathway alterations were detected in 80 (24.4%) of 328 patients: NF1 (n=7, 2.1%), PTPN11 (n=15, 4.6%), CBL (n=6, 1.8%), NRAS (n=44, 13.4%), KRAS (n=12, 3.7%). Most of these alterations in the RAS pathway were mutually exclusive also together with other aberrations of signal transduction pathways such as FLT3-ITD (P=0.001) and KIT mutation (P=0.004). NF1 alterations were frequently detected in patients with complex karyotype (P=0.031) and were found to be independent predictors of poor overall survival (OS) in multivariate analysis (P=0.007). At least four of seven patients with NF1 alterations had biallelic inactivation. NRAS mutations were frequently observed in patients with CBFB-MYH11 and were independent predictors of favorable outcomes in multivariate analysis (OS, P=0.023; event-free survival [EFS], P=0.037). Patients with PTPN11 mutations more frequently received stem cell transplantation (P=0.035) and showed poor EFS than patients without PTPN11 mutations (P=0.013). Detailed analysis of RAS pathway alterations may enable a more accurate prognostic stratification of pediatric AML and may provide novel therapeutic molecular targets related to this signal transduction pathway.

Japanese travel behavior trends and change under COVID-19 state-of-emergency declaration: Nationwide observation by mobile phone location data.

In the early stages of the COVID-19 pandemic, the Japan government could not impose strong restrictions such as lockdowns. Since there has been no such nation-wide behavioral analysis, we calculated indicators of nation-wide behavioral change using data based on mobile phone network.This study shows empirical facts and findings on behavioral changes under COVID-19 "state-of-emergency" declarations in Japan that are obtained by using mobile terminal network operational data. Results show that a significant reduction in trips and inter-prefectural travel was achieved without strong restrictions by the government. In addition, the population density index decreased by 20% and people avoided traveling to densely populated areas. This analysis shows that once people's behavior is changed by the declaration of a state of emergency, it does not return to normal immediately after the lifting of the declaration; rather, it recovers slowly.

Droplet digital polymerase chain reaction assay for the detection of the minor clone of KIT D816V in paediatric acute myeloid leukaemia especially showing RUNX1-RUNX1T1 transcripts.

KIT D816V mutation within exon 17 has been particularly reported as one of the poor prognostic factors in pediatric acute myeloid leukemia (AML) with RUNX1-RUNX1T1. The exact frequency and the prognostic impact of KIT D816V minor clones at diagnosis were not examined. In this study, the minor clones were examined and the prognostic significance of KIT D816V mutation in pediatric patients was investigated. Consequently, 24 KIT D816V mutations (7.2%) in 335 pediatric patients were identified, and 12 of 24 were only detected via the digital droplet polymerase chain reaction method. All 12 patients were confined in core binding factor (CBF)-AML patients. The 5 year event-free survival of the patients with KIT D816V mutation was significantly inferior to those without KIT D816V mutation (44.1% [95% confidence interval (CI), 16.0%-69.4%] vs. 74.7% [95% CI, 63.0%-83.2%] P-value = 0.02, respectively). The 5 year overall survival was not different between the two groups (92.9% [95% CI, 59.0%-NA vs. 89.7% [95% CI, 69.6%-96.8%] P-value = 0.607, respectively). In this study, KIT D816V minor clones in patients with CBF-AML were confirmed and KIT D816V was considered as a risk factor for relapse in patients with RUNX1-RUNX1T1-positive AML.

JRAB/MICAL-L2 undergoes liquid-liquid phase separation to form tubular recycling endosomes.

Elongated tubular endosomes play essential roles in diverse cellular functions. Multiple molecules have been implicated in tubulation of recycling endosomes, but the mechanism of endosomal tubule biogenesis has remained unclear. In this study, we found that JRAB/MICAL-L2 induces endosomal tubulation via activated Rab8A. In association with Rab8A, JRAB/MICAL-L2 adopts its closed form, which functions in the tubulation of recycling endosomes. Moreover, JRAB/MICAL-L2 induces liquid-liquid phase separation, initiating the formation of tubular recycling endosomes upon overexpression. Between its N-terminal and C-terminal globular domains, JRAB/MICAL-L2 contains an intrinsically disordered region, which contributes to the formation of JRAB/MICAL-L2 condensates. Based on our findings, we propose that JRAB/MICAL-L2 plays two sequential roles in the biogenesis of tubular recycling endosomes: first, JRAB/MICAL-L2 organizes phase separation, and then the closed form of JRAB/MICAL-L2 formed by interaction with Rab8A promotes endosomal tubulation.

Effects of Fiber Stiffening to a Soft Actuator with PEDOT/PSS Electrode Films on Actuation Cycling Stability.

In this work, we fabricated a fiber-stiffened soft actuator with PEDOT/PSS films as electrode. Embedding nylon fibers in the soft actuator successfully suppressed twisting deformations, resulting in a large and persistent actuation displacement. We evaluated the effects of the fiber spacing (1, 2, 3 and 4 mm) on the displacement and assessed the actuation displacement as a function of applied voltage (0.5, 1.0 and 1.5 V) and frequency (0.2 and 1 Hz) with an actuation time of 500 s. We demonstrated that the fiberstiffened actuator with 2 mm fiber spacing exhibited steady actuation cycles (4.2 mm average displacement) in comparison with those with different spacings (1, 3, and 4 mm) and that without the fiber.

Effects of Food and Temperature on Drosophila melanogaster Reproductive Dormancy as Revealed by Quantification of a GFP-Tagged Yolk Protein in the Ovary.

When exposed to harsh environmental conditions, such as food scarcity and/or low temperature, Drosophila melanogaster females enter reproductive dormancy, a metabolic state that enhances stress resistance for survival at the expense of reproduction. Although the absence of egg chambers carrying yolk from the ovary has been used to define reproductive dormancy in this species, this definition is susceptible to false judgements of dormancy events: e.g. a trace amount of yolk could escape visual detection; a fly is judged to be in the non-dormancy state if it has a single yolk-containing egg chamber even when other egg chambers are devoid of yolk. In this study, we propose an alternative method for describing the maturation state of oocytes, in which the amount of yolk in the entire ovary is quantified by the fluorescence intensity derived from GFP, which is expressed as a fusion with the major yolk protein Yp1. We show that yolk deposition increases with temperature with a sigmoidal function, and the quality of food substantially alters the maximum accumulation of yolk attainable at a given temperature. The Yp1::GFP reporter will serve as a reliable tool for quantifying the amount of yolk and provides a new means for defining the dormancy state in D. melanogaster.