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Abstract The Wnt/β-catenin signaling pathway is crucial for embryonic development and adult tissue homeostasis. Dysregulation of Wnt signaling is linked to various developmental anomalies and diseases, notably cancer. Although numerous regulators of the Wnt signaling pathway have been identified, their precise function during mouse embryo development remains unclear. Here, we revealed that TMEM132A is a crucial regulator of canonical Wnt/β-catenin signaling in mouse development. Mouse embryos lacking Tmem132a displayed a range of malformations, including open spina bifida, caudal truncation, syndactyly, and renal defects, similar to the phenotypes of Wnt/β-catenin mutants. Tmem132a knockdown in cultured cells suppressed canonical Wnt/β-catenin signaling. In developing mice, loss of Tmem132a also led to diminished Wnt/β-catenin signaling. Mechanistically, we showed that TMEM132A interacts with the Wnt co-receptor LRP6, thereby stabilizing it and preventing its lysosomal degradation. These findings shed light on a novel role for TMEM132A in regulating LRP6 stability and canonical Wnt/β-catenin signaling during mouse embryo development. This study provides valuable insights into the molecular intricacies of the Wnt signaling pathway. Further research may deepen our understanding of Wnt pathway regulation and offer its potential therapeutic applications.

Sensitive skin (SS) is associated with discomfort, including burning, stinging, and itching. These symptoms are often exacerbated by environmental factors and personal care products. In this genome-wide association study (GWAS), we aimed to identify the genetic variants associated with SS in 1690 Korean female participants; 389 and 1301 participants exhibited sensitive and non-sensitive skin, respectively. Using a combination of self-reported questionnaires, patch tests, and sting tests, we selected 115 sensitive and 181 non-sensitive participants for genetic analysis. A GWAS was performed to identify the loci associated with SS. Although none of the single-nucleotide polymorphisms (SNPs) met the genome-wide significance threshold, we identified several SNPs with suggestive associations. SNP rs11689992 in the 2q11.3 region increased SS risk by approximately 3.67 times. SNP rs7614738 in the USP4 locus elevated SS risk by 2.34 times and was found to be an expression quantitative trait locus for GPX1, a gene involved in oxidative stress and inflammation. Additionally, SNPs rs12306124 in the RASSF8 locus and rs10483893 in the NRXN3 region were identified. These results suggest that the genetic variations affecting oxidative stress, cell growth regulation, and neurobiology potentially influence skin sensitivity, providing a basis for further investigation and the development of personalized approaches to manage sensitive skin.

Securinega alkaloids have intrigued chemists since the isolation of securinine in 1956. This family of natural products comprises a securinane subfamily with a piperidine substructure and norsecurinane alkaloids featuring a pyrrolidine core. From a biosynthetic perspective, the piperidine moiety in securinane alkaloids derives from lysine, whereas the pyrrolidine moiety in norsecurinane natural products originates from ornithine, marking an early biogenetic divergence. Herein, we introduce a single-atom deletion strategy that enables the late-stage conversion of securinane to norsecurinane alkaloids. Notably, for the first time, this method enabled the transformation of piperidine-based (allo)securinine into pyrrolidine-based (allo)norsecurinine. Straightforward access to norsecurinine from securinine, which can be readily extracted from the plant Flueggea suffruticosa, abundant across the Korean peninsula, holds promise for synthetic studies of norsecurinine-based oligomeric securinega alkaloids.

Abstract With the power conversion efficiency of binary polymer solar cells dramatically improved, the thermal stability of the small-molecule acceptors raised the main concerns on the device operating stability. Here, to address this issue, thiophene-dicarboxylate spacer tethered small-molecule acceptors are designed, and their molecular geometries are further regulated via the thiophene-core isomerism engineering, affording dimeric TDY-α with a 2, 5-substitution and TDY-β with 3, 4-substitution on the core. It shows that TDY-α processes a higher glass transition temperature, better crystallinity relative to its individual small-molecule acceptor segment and isomeric counterpart of TDY-β, and a more stable morphology with the polymer donor. As a result, the TDY-α based device delivers a higher device efficiency of 18.1%, and most important, achieves an extrapolated lifetime of about 35000 hours that retaining 80% of their initial efficiency. Our result suggests that with proper geometry design, the tethered small-molecule acceptors can achieve both high device efficiency and operating stability.

We introduce a GPU-accelerated hybrid hydro/ N -body code ( Enzo-N ) designed to address the challenges of concurrently simulating star clusters and their parent galaxies. This task has been exceedingly challenging, primarily due to the considerable computational time required, which stems from the substantial scale difference between galaxies (∼0.1 Mpc) and star clusters (∼parsecs). Yet, this significant scale separation means that particles within star clusters perceive those outside the star cluster in a semistationary state. By leveraging this aspect, we integrate a direct N -body code ( Nbody6++GPU ) into a cosmological (magneto)hydrodynamic code ( Enzo ) through utilization of the semistationary background acceleration approximation. We solve the dynamics of particles within star clusters using a direct N -body solver with regularization for few-body interactions, while evolving particles outside—dark matter, gas, and stars—using a particle-mesh gravity solver and hydrodynamic methods. We demonstrate that Enzo-N successfully simulates the coevolution of star clusters and their parent galaxies, capturing phenomena such as core collapse of the star cluster and tidal stripping due to galactic tides. This comprehensive framework opens up new possibilities for studying the evolution of star clusters within galaxies, offering insights that were previously inaccessible.

Abstract The dopamine blockade by antipsychotics trigger subjective dysphoria. Compared with D2 antagonists, aripiprazole, a D2 partial agonist, was expected to produce a different experience. Indeed, a previous study reported no relationship between the D2 receptor occupancy by aripiprazole and subjective dysphoria, while the D2 receptor occupancy by antagonists was associated with negative subjective experiences. This study revisited the relationship in patients treated with aripiprazole by using an inhibitory Emax model, which enables the individual drug-free binding potential and D2 receptor occupancy to be properly estimated. Eight patients with schizophrenia who have been clinically stable on aripiprazole were enrolled. Assessments including Positive and Negative Syndrome Scale (PANSS) and Subjective Well-being under Neuroleptics Scale (Kv-SWN) were administered. [11C]raclopride PET scan were conducted 2, 26, and 74 h after aripiprazole administration. Regression analysis showed a significant negative association between the D2 receptor occupancy by aripiprazole in the striatum and the Kv-SWN (R2 = 0.55, p = 0.036), but the PANSS total score was not associated with the Kv-SWN (R2 = 0.42, p = 0.080). The negative association between D2 receptor occupancy by aripiprazole and subjective well-being implies that clinicians should find the lowest effective doses of aripiprazole for clinically stable patients to improve their subjective experiences and clinical outcomes.

Abstract This study explores how South Korean individuals managed the impacts of the COVID-19 pandemic in their daily lives during a time of continuous and sustained social distancing using 8241 Instagram posts from May 6 to June 16, 2020. Co-word analysis found two main theme clusters highlighting individuals’ endeavors in daily life management and their fear of COVID-19 infection. DMR topic modeling analysis resulted in five higher-order themes, each reflecting different aspects of people’s COVID-19 experiences. Overall, the results shed light on individuals’ resilience in managing their daily lives despite the fear and discomfort caused by the pandemic. Results also highlight the possibility that the discursive practices of Social Network Services (SNS) reinforce hatred against social minorities and frame otherizing COVID-19 patients as legitimate. The present study suggests the need for a range of social support to help individuals and communities during the prolonged pandemic, including a long-term, large-scale psychological quarantine system. Deliberate social measures also need to be taken to promote the process of social sharing through media texts and SNS to resist hateful frames and othering of social minorities. Limitations of the study and suggestions for future research are provided.

Whereas most previous studies on (super-)gang effects examined cases where two weaker constraints jointly beat another stronger constraint (Albright 2012; Shih 2017; Breiss & Albright 2022), this paper addresses gang effects that arise from multiple violations of a single constraint, which Jäger & Rosenbach (2006) referred to as counting cumulativity. The super-additive version of counting cumulativity is the focus of this paper; cases where multiple violations of a weaker constraint not only overpower a single violation of a stronger constraint, but also surpass the mere multiplication of the severity of its single violation. I report two natural language examples where a morphophonological alternation in a compound is suppressed by the existence of marked segments in a super-additive manner: laryngeally marked consonants in Korean compound tensification and nasals in Japanese Rendaku. Using these two test cases, this paper argues that these types of super-additivity cannot be entirely captured by the traditional MaxEnt grammar; instead, a modified MaxEnt model is proposed, in which the degree of penalty is scaled up by the number of violations, through a power function. This paper also provides a computational implementation of the proposed MaxEnt model which learns necessary parameters given quantitative language data. A series of learning simulations on Korean and Japanese show that the MaxEnt learner is able to detect super-additive constraints and find the appropriate exponent values for those, correctly capturing the probability distributions in the input data.

Objectives Although unilateral hearing loss (UHL) has been proven to be associated with educational and behavioral problems, few studies have investigated psychopathological abnormalities in this population. The aim of this study was to evaluate the psychopathological influence of UHL among Korean 19-year-old males. Methods The authors retrospectively compared the objective personality test profiles of 602 subjects with UHL with those of 23,790 peers with normal hearing. All participants in the current study were 19-year-old males who underwent a physical examination and completed the Korean Military Multiphasic Personality Inventory for conscription at the Military Manpower Administration from February 2015 to December 2016. Results Significantly higher scores were found on neurosis scales in the UHL group than in the normal-hearing group (50.9± 10.8 vs. 44.9±6.0 for anxiety; 51.0±10.5 vs. 44.9±5.2 for depression; 51.1±10.4 vs. 45.1±6.81 for somatization, all P

Objective Most patients with rheumatoid arthritis (RA) strive to consolidate their treatment from methotrexate combinations. The objective of this analysis was to identify patients with RA most likely to achieve remission with tocilizumab (TCZ) monotherapy by developing and validating a prediction model and associated remission score. Methods We identified four TCZ monotherapy randomized controlled trials in RA and chose two for derivation and two for internal validation. Remission was defined as a Clinical Disease Activity Index score less than 2.8 at 24 weeks post randomization. We used logistic regression to assess the association between each predictor and remission. After selecting variables and assessing model performance in the derivation data set, we assessed model performance in the validation data set. The cohorts were combined to calculate a remission prediction score. Results The variables selected included younger age, male sex, lower baseline Clinical Disease Activity Index score, shorter RA disease duration, region of the world (Europe and South America [increased odds of remission] versus Asia and North America), no previous exposure to disease‐modifying antirheumatic drugs and/or methotrexate, lower baseline Health Assessment Questionnaire Disability Index score, and baseline hematocrit. The area under the receiver operating characteristic curve was 0.739 in the derivation data set and 0.756 in the validation data set. Patients were categorized into three remission prediction categories based on the remission prediction score: 40% in the low (less than 10% probability of remission), 45% in the intermediate (10%‐25% probability), and 15% in the moderate remission prediction category (greater than 25% probability). Conclusion We used easily accessible factors to develop a remission prediction score to predict RA remission at 24 weeks after initializing TCZ monotherapy. These results may provide guidance to clinicians tailoring treatment options based on clinical characteristics.

Hydroxyethyl cellulose (HEC), widely known for its biocompatibility and water solubility, is a polysaccharide with potential for pharmaceutical applications. Here, we synthesized polyethylenimine2k (PEI2k)-conjugated hydroxyethyl cellulose (HECP2k) for doxorubicin/Bcl-2 siRNA co-delivery systems. HECP2ks were synthesized by reductive amination of PEI2k with periodate-oxidized HEC. The synthesis of the polymers was characterized using 1H NMR, 13C NMR, primary amine quantification, FT-IR, and GPC. Via agarose gel electrophoresis and Zeta-sizer measurement, it was found that HECP2ks condensed pDNA to positively charged and nano-sized complexes (100–300 nm, ~30 mV). The cytotoxicity of HECP2ks was low and HECP2k 10X exhibited higher transfection efficiency than PEI25k even in serum condition, showing its high serum stability from ethylene oxide side chains. Flow cytometry analysis and confocal laser microscopy observation verified the superior cellular uptake and efficient endosome escape of HECP2k 10X. HECP2k 10X also could load Dox and Bcl-2 siRNA, forming nano-particles (HECP2k 10X@Dox/siRNA). By median effect analysis and annexin V staining analysis, it was found that HECP2k 10X@Dox/siRNA complexes could cause synergistically enhanced anti-cancer effects to cancer cells via induction of apoptosis. Consequently, it was concluded that HECP2k possesses great potential as a promising Dox/Bcl-2 siRNA co-delivery carrier.

The purpose of this study is to identify the relationship between drainage density and climate, as represented by the climate aridity index, and to understand the relationship between drainage density and drainage area. A total of 121 study sites with low human impact, and a wide range of climate aridity index 0.3 (humid)–10.4 (arid), were selected based on the availability of light detection and ranging (LiDAR) data, producing a digital elevation model (DEM) with a spatial resolution of 1 m. A curvature-based method, incorporating both positive and negative curvature information, was used to extract the valley (drainage) network from the LiDAR-based DEMs. Drainage density and climate aridity index exhibited a monotonically increasing trend, contrary to the previous results that have shown a U-shaped relationship. This discrepancy was caused by the selection of watersheds with extensive human activity in the previous study. One-meter resolution DEM produced greater drainage density than the previous studies with a coarse spatial resolution of 30 m as small valleys are not detectable in low-resolution topography datasets. The discrepancy between the previous study and the current study results encouraged further investigation of the impact of the drainage area (watershed size). A negative correlation between drainage density and drainage area was reconfirmed, while a stronger decreasing trend was observed in arid regions than in humid regions.

This study assesses the characteristics of perennial streams using the dimensionless relationship between streamflow exceedance probability and the wet channel ratio based on a wet channel network extracted from light detection and ranging (LiDAR) data. LiDAR provides topographic data and signals’ intensity in high-resolution and with high accuracy to provide useful information for drainage networks and channel network extraction. In this study, a valley network and wet channel are extracted from LiDAR topographic and signals’ intensity information with a spatial resolution of 1 meter. Based on the available LiDAR data and streamflow observations from across the United States, we selected 30 watersheds with various climate conditions and analyzed the characteristics of their perennial streams. The wet channel ratio and perennial stream ratio were developed to define a perennial stream using the observed streamflow and the identified wet channel. The results of this study are consistent with previous studies on the definition of a perennial stream through transformation into a dimensionless form and confirmed the possibility of applying the wet channel ratio as an alternative parameter to define a perennial stream.

Background Polydeoxyribonucleotide (PDRN) is known to have anti-inflammatory and angiogenic effects and to accelerate wound healing. The aim of this study was to investigate whether PDRN could improve peripheral tissue oxygenation and angiogenesis in diabetic foot ulcers. Methods This was a prospective randomized controlled clinical trial. Twenty patients with a non-healing diabetic foot ulcer were randomly distributed into a control group (n=10) and a PDRN group (n=10). Initial surgical debridement and secondary surgical procedures such as a split-thickness skin graft, primary closure, or local flap were performed. Between the initial surgical debridement and secondary surgical procedures, 0.9% normal saline (3 mL) or PDRN was injected for 2 weeks by the intramuscular (1 ampule, 3 mL, 5.625 mg, 5 days per week) and perilesional routes (1 ampule, 3 mL, 5.625 mg, 2 days per week). Transcutaneous oxygen tension (TcPO2) was evaluated using the Periflux System 5000 with TcPO2/CO2 unit 5040 before the injections and on days 1, 3, 7, 14, and 28 after the start of the injections. A pathologic review (hematoxylin and eosin stain) of the debrided specimens was conducted by a pathologist, and vessel density (average number of vessels per visual field) was calculated. Results Compared with the control group, the PDRN-treated group showed improvements in peripheral tissue oxygenation on day 7 (P

Tuberculosis infection exhibits different forms, namely, pulmonary, extrapulmonary, and latent. Here, diagnostic markers based on the gene expression of cytokines and chemokines for differentiating between tuberculosis infection state(s) were identified. Gene expression of seven cytokines (Interferon gamma (IFN-γ), Interferon gamma-induced protein 10 (IP-10), Interleukin-2 receptor (IL-2R), C-X-C Motif Chemokine Ligand 9 (CXCL-9), Interleukin 10 (IL-10), Interleukin 4 (IL-4), and Tumor Necrosis Factor alpha (TNF-α)) in response to tuberculosis antigen was analyzed using real-time polymerase reaction. The sensitivity and specificity of relative quantification (2^-ΔΔCt) of mRNA expression were analyzed by constructing receiver operating characteristic curves and measuring the area under the curve (AUC) values. Combinations of cytokines were analyzed using the R statistical software package. IFN-γ, IP-10, IL2R, and CXCL-9 showed high expression in latent and active tuberculosis patients (p = 0.001), with a decrease in IL10 expression, and no statistical difference in IL-4 levels among all the groups (p = 0.999). IL-10 differentiated pulmonary tuberculosis patients from latent cases with an AUC of 0.731. IL10 combined with CXCL-9 distinguished pulmonary tuberculosis patients from extrapulmonary cases with a sensitivity, specificity, and accuracy of 85.7%, 73.9%, and 81.0%, respectively. IL-10 together with IP-10 and IL-4 differentiated pulmonary tuberculosis from latent cases with a sensitivity and specificity of 77.1% and 88.1%, respectively. Decision tree analysis demonstrated that IFN-γ IL-2R, and IL-4 can diagnose tuberculosis infection with a sensitivity, specificity, and accuracy of 89.7%, 96.1%, and 92.7%, respectively. A combination of gene expression of cytokines and chemokines might serve as an effective marker to differentiate tuberculosis infection state(s).

As demands for health and wellbeing in the ageing society have grown, complex problems involving diverse stakeholders arise in the healthcare environment. The objective of this study is to identify roles and abilities of designers in a healthcare setting where professionals from different disciplines collaborate to achieve a common goal. Case studies on healthcare design projects adapting interdisciplinary approach were explored to find which methods and processes were implemented effectively. Results are based on three research questions that lead to analyzing multifaceted roles of designers regarding process facilitation, manage relations, visualization, and imagination. [ABSTRACT FROM AUTHOR]

For a pair (E,P) of an elliptic curve E/Q and a nontorsion point P Ⲉ E(Q), the sequence of elliptic Fermat numbers is defined by taking quotients of terms in the corresponding elliptic divisibility sequence (Dn)nⲉN with index powers of two, i.e. D1, D2/D1, D4/D2, etc. Elliptic Fermat numbers share many properties with the classical Fermat numbers, Fk = 2²k + 1. In the present paper, we show that for magnified elliptic Fermat sequences, only finitely many terms are prime. We also define generalized elliptic Fermat numbers by taking quotients of terms in elliptic divisibility sequences that correspond to powers of any odd positive integer m, and show that many of the classical properties of Fermat numbers, including coprimality, order universality, and compositeness, still hold. [ABSTRACT FROM AUTHOR]

Special investment vehicles (SIVs), extremely popular financial structures for the creation of highly-rated tranched securities, experienced spectacular demise in the 2007-2008 financial crisis. These financial vehicles epitomize the shadow banking sector, characterized by high leverage, undiversified asset pools, and long-dated assets supported by short-term debt, thus bearing material rollover risk on their liabilities which led to defeasance. This paper models these vehicles, and shows that imposing leverage risk control triggers can be optimal for all capital providers, though they may not always be appropriate. The efficacy of these risk controls varies depending on anticipated asset volatility and fire-sale discounts on defeasance. Despite risk management controls, we show that a high failure rate is inherent in the design of these vehicles, and may be mitigated to some extent by including contingent capital provisions in the ex-ante covenants. Post the recent subprime financial crisis, we inform the creation of safer SIVs in structured finance, and propose avenues of mitigating risks faced by senior debt through deleveraging policies in the form of leverage risk controls and contingent capital. [ABSTRACT FROM AUTHOR]

The authors present a liability-directed investment (LDI) rebalancing framework that is based on expected shortfall (ES), denoted as LDI-ES, to prescribe remedies for an underfunded portfolio. Investors endowed with some current wealth optimize their target wealth at the end of N periods, subject to their tolerance for shortfalls from that target wealth. The authors contrast LDI-ES rebalancing with fixed-proportions rebalancing, in which portfolio allocations are rebalanced to ratios, such as 60:40, at the beginning of each of N periods. They consider critical issues of underfunding, in which no portfolio can meet the shortfall constraint, as well as the effectiveness of portfolio infusions in resolving underfunded situations relative to other measures, such as increasing risk, cutting back on target liabilities or goals, and extending the portfolio horizon. [ABSTRACT FROM AUTHOR]

The article discusses genomics research of the roles of the conserved kinases Mps1 and Ipl1/Aurora B in enabling chromosomes to attach to microtubules to allow for chromosomal segregation. Topics include the study of the stages of chromosome-microtubule interactions in live yeast cells; the role of Ipl1 and Mps1 in meiosis; and the effects of the microtubule release and reattachment cycle on chromosome segregation errors. Spindle interactions by chromosome pairs are discussed, with a focus on the release of kinetochore-microtubule (kMT) associations due to the presence of Ipl1 on the meiotic spindle of budding yeast.

Background: Evaluation of skin sensitization potential is an important part of the safety assessment of cosmetic ingredients and topical drugs. Recently, evaluation of changes in surface marker expression induced in dendritic cells (DC) or DC surrogate cell lines following exposure to chemicals represents one approach for in vitro test methods. Objective: The study aimed to test the change of expression patterns of surface markers on THP-1 cells by chemicals as a predictive in vitro method for contact sensitization. Methods: We investigated the expression of CD54, CD86, CD83, CD80, and CD40 after a 1-day exposure to sensitizers (1-chloro-2,4-dinitrobenzene; 2,4-dinitrofluorobenzene; benzocaine; 5-chloro-2-methyl-4-isothiazolin-3-one; hexyl cinnamic aldehyde; eugenol; nickel sulfate hexahydrate; potassium dichromate; cobalt sulfate; 2-mercaptobenzothiazole; and ammonium tetrachloroplatinate) and non-sensitizers (sodium lauryl sulfate, benzalkonium chloride, lactic acid, salicylic acid, isopropanol, and dimethyl sulphoxide). The test concentrations were 0.1×, 0.5×, and 1× of the 50% inhibitory concentration, and the relative fluorescence intensity was used as an expression indicator. Result and Conclusion: By evaluating the expression patterns of CD54, CD86, and CD40, we could classify the chemicals as sensitizers or non-sensitizers, but CD80 and CD83 showed non-specific patterns of expression. These data suggest that the THP-1 cells are good model for screening contact sensitizers and CD40 could be a useful marker complementary to CD54 and CD86. [ABSTRACT FROM AUTHOR]