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Abstract Genetic neuromuscular diseases are clinically and genetically heterogeneous genetic disorders that primarily affect the peripheral nerves, muscles, and neuromuscular junctions. This study aimed to identify pathogenic variants, calculate carrier frequency, and predict the genetic prevalence of autosomal recessive neuromuscular diseases (AR-NMDs). We selected 268 AR-NMD genes and analyzed their genetic variants sourced from the gnomAD database. After identifying the pathogenic variants using an algorithm, we calculated the carrier frequency and predicted the genetic prevalence of AR-NMDs. In total, 10,887 pathogenic variants were identified, including 3848 literature verified and 7039 manually verified variants. In the global population, the carrier frequency of AR-NMDs is 32.9%, with variations across subpopulations ranging from 22.4% in the Finnish population to 36.2% in the non-Finnish European population. The predicted genetic prevalence of AR-NMDs was estimated to be 24.3 cases per 100,000 individuals worldwide, with variations across subpopulations ranging from 26.5 to 41.4 cases per 100,000 individuals in the Latino/Admixed American and the Ashkenazi Jewish populations, respectively. The AR-NMD gene with the highest carrier frequency was GAA (1.3%) and the variant with the highest allele frequency was c.-32-13 T>G in GAA with 0.0033 in the global population. Our study revealed a higher-than-expected frequency of AR-NMD carriers, constituting approximately one-third of the global population, highlighting ethnic heterogeneity in genetic susceptibility.

Abstract Background Although the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML. Methods We generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3+ CML patients. Results We reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3+ BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3+ BP-CML patients had significantly less favorable prognosis than FLT3− patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3+ BCR::ABL1 cells and mouse xenograft models. Conclusion Here, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies. Graphical Abstract

Abstract In a patient diagnosed with both Kallmann syndrome (KS) and intellectual disability (ID), who carried an apparently balanced translocation t(7;12)(q22;q24)dn, array comparative genomic hybridization (aCGH) disclosed a cryptic heterozygous 4.7 Mb deletion del(12)(p11.21p11.23), unrelated to the translocation breakpoint. This novel discovery prompted us to consider the possibility that the combination of KS and neurological disorder in this patient could be attributed to gene(s) within this specific deletion at 12p11.21-12p11.23, rather than disrupted or dysregulated genes at the translocation breakpoints. To further support this hypothesis, we expanded our study by screening five candidate genes at both breakpoints of the chromosomal translocation in a cohort of 48 KS patients. However, no mutations were found, thus reinforcing our supposition. In order to delve deeper into the characterization of the 12p11.21-12p11.23 region, we enlisted six additional patients with small copy number variations (CNVs) and analyzed eight individuals carrying small CNVs in this region from the DECIPHER database. Our investigation utilized a combination of complementary approaches. Firstly, we conducted a comprehensive phenotypic-genotypic comparison of reported CNV cases. Additionally, we reviewed knockout animal models that exhibit phenotypic similarities to human conditions. Moreover, we analyzed reported variants in candidate genes and explored their association with corresponding phenotypes. Lastly, we examined the interacting genes associated with these phenotypes to gain further insights. As a result, we identified a dozen candidate genes: TSPAN11 as a potential KS candidate gene, TM7SF3, STK38L, ARNTL2, ERGIC2, TMTC1, DENND5B, and ETFBKMT as candidate genes for the neurodevelopmental disorder, and INTS13, REP15, PPFIBP1, and FAR2 as candidate genes for KS with ID. Notably, the high-level expression pattern of these genes in relevant human tissues further supported their candidacy. Based on our findings, we propose that dosage alterations of these candidate genes may contribute to sexual and/or cognitive impairments observed in patients with KS and/or ID. However, the confirmation of their causal roles necessitates further identification of point mutations in these candidate genes through next-generation sequencing.

Abstract Atmospheric turbulence at commercial aircraft cruising altitudes is a main threat to aviation safety worldwide. As the air transport industry expands and is continuously growing, investigating global response of aviation turbulence under climate change scenarios is required for preparing optimal and safe flying plans for the future. This study examines future frequencies of moderate-or-greater-intensity turbulence generated from various sources, viz., clear-air turbulence and mountain-wave turbulence that are concentrated in midlatitudes, and near-cloud turbulence that is concentrated in tropics and subtropics, using long-term climate model data of high-emissions scenario and historical condition. Here, we show that turbulence generated from all three sources is intensified with higher occurrences globally in changed climate compared to the historical period. Although previous studies have reported intensification of clear-air turbulence in changing climate, implying bumpier flights in the future, we show that intensification of mountain-wave turbulence and near-cloud turbulence can also be expected with changing climate.

Abstract WDR11, a gene associated with Kallmann syndrome, is important in reproductive system development but molecular understanding of its action remains incomplete. We previously reported that Wdr11-deficient embryos exhibit defective ciliogenesis and developmental defects associated with Hedgehog (HH) signalling. Here we demonstrate that WDR11 is required for primordial germ cell (PGC) development, regulating canonical and noncanonical HH signalling in parallel. Loss of WDR11 disrupts PGC motility and proliferation driven by the cilia-independent, PTCH2/GAS1-dependent noncanonical HH pathway. WDR11 modulates the growth of somatic cells surrounding PGCs by regulating the cilia-dependent, PTCH1/BOC-dependent canonical HH pathway. We reveal that PTCH1/BOC or PTCH2/GAS1 receptor context dictates SMO localisation inside or outside of cilia, respectively, and loss of WDR11 affects the signalling responses of SMO in both situations. We show that GAS1 is induced by PTCH2-specific HH signalling, which is lost in the absence of WDR11. We also provide evidence supporting a role for WDR11 in ciliogenesis through regulation of anterograde intraflagellar transport potentially via its interaction with IFT20. Since WDR11 is a target of noncanonical SMO signalling, WDR11 represents a novel mechanism by which noncanonical and canonical HH signals communicate and cooperate.

Abstract Atomic layer deposition (ALD) has become the most widely used thin‐film deposition technique in various fields due to its unique advantages, such as self‐terminating growth, precise thickness control, and excellent deposition quality. In the energy storage domain, ALD has shown great potential for supercapacitors (SCs) by enabling the construction and surface engineering of novel electrode materials. This review aims to present a comprehensive outlook on the development, achievements, and design of advanced electrodes involving the application of ALD for realizing high‐performance SCs to date, as organized in several sections of this paper. Specifically, this review focuses on understanding the influence of ALD parameters on the electrochemical performance and discusses the ALD of nanostructured electrochemically active electrode materials on various templates for SCs. It examines the influence of ALD parameters on electrochemical performance and highlights ALD's role in passivating electrodes and creating 3D nanoarchitectures. The relationship between synthesis procedures and SC properties is analyzed to guide future research in preparing materials for various applications. Finally, it is concluded by suggesting the directions and scope of future research and development to further leverage the unique advantages of ALD for fabricating new materials and harness the unexplored opportunities in the fabrication of advanced‐generation SCs.

Single atom catalysts not only maximize the atomic efficiency of noble metal but also introduce unconventional geometric and electronic structures. Here, the authors demonstrate the decoration of iridium single atoms on silicon photoanodes to boost the photogenerated charge carrier kinetics.

(1) Background: Non-invasive prenatal testing (NIPT) is a screening test for fetal aneuploidy using cell-free fetal DNA. The fetal fragments (FF) of cell-free DNA (cfDNA) are derived from apoptotic trophoblast of the placenta. The level of fetal cfDNA is known to be influenced by gestational age, multiple pregnancies, maternal weight, and height. (2) Methods: This study is a single-center retrospective observational study which examines the relationship between the fetal fraction (FF) of cell-free DNA in non-invasive prenatal testing (NIPT) and adverse pregnancy outcomes in singleton pregnancies. A total of 1393 samples were collected between 10 weeks and 6 days, and 25 weeks and 3 days of gestation. (3) Results: Hypertensive disease of pregnancy (HDP) occurred more frequently in the low FF group than the normal FF group (5.17% vs. 1.91%, p = 0.001). Although the rates of small for gestational age (SGA) and placental abruption did not significantly differ between groups, the composite outcome was significantly higher in the low FF group (7.76% vs. 3.64%, p = 0.002). Furthermore, women who later experienced complications such as HDP or gestational diabetes mellitus (GDM) had significantly lower plasma FF levels compared to those without complications (p < 0.001). After adjustments, the low FF group exhibited a significantly higher likelihood of placental compromise (adjusted odds ratio: 1.946). (4) Conclusions: Low FF in NIPT during the first and early second trimesters is associated with adverse pregnancy outcomes, particularly HDP, suggesting its potential as a predictive marker for such outcomes.

Abstract An electron probe X-ray microanalyzer (EPMA) is an essential tool for studying chemical composition distribution in the microstructure. Quantifying chemical composition using standard specimens is commonly used to determine the composition of individual phases. However, the local difference in chemical composition in the standard specimens brings the deviation of the quantified composition from the actual one. This study introduces how to overcome the error of quantification in EPMA in the practical aspect. The obtained results are applied to evaluate the chemical composition of retained austenite in multi-phase steel. Film-type austenite shows higher carbon content than blocky-type one. The measured carbon contents of the retained austenite show good coherency with the calculated value from the X-ray diffraction.

Abstract Cobll1 affects blast crisis (BC) progression and tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML). PACSIN2, a novel Cobll1 binding protein, activates TKI‐induced apoptosis in K562 cells, and this activation is suppressed by Cobll1 through the interaction between PACSIN2 and Cobll1. PACSIN2 also binds and inhibits SH3BP1 which activates the downstream Rac1 pathway and induces TKI resistance. PACSIN2 competitively interacts with Cobll1 or SH3BP1 with a higher affinity for Cobll1. Cobll1 preferentially binds to PACSIN2, releasing SH3BP1 to promote the SH3BP1/Rac1 pathway and suppress TKI‐mediated apoptosis and eventually leading to TKI resistance. Similar interactions among Cobll1, PACSIN2, and SH3BP1 control hematopoiesis during vertebrate embryogenesis. Clinical analysis showed that most patients with CML have Cobll1 and SH3BP1 expression at the BC phase and BC patients with Cobll1 and SH3BP1 expression showed severe progression with a higher blast percentage than those without any Cobll1, PACSIN2, or SH3BP1 expression. Our study details the molecular mechanism of the Cobll1/PACSIN2/SH3BP1 pathway in regulating drug resistance and BC progression in CML.

Abstract In searching for unique and unexplored 2D materials, the authors try to investigate for the very first time the use of delaminated V‐MXene coupled with precious metal ruthenium (Ru) through atomic layer deposition (ALD) for various contact and noncontact mode of real‐time temperature sensing applications at the human–machine interface. The novel delaminated V‐MXene (DM‐V2CTx) engineered ruthenium‐ALD (Ru‐ALD) temperature sensor demonstrates a competitive sensing performance of 1.11% °C−1 as of only V‐MXene of 0.42% °C−1. A nearly threefold increase in sensing and reversibility performance linked to the highly ordered few‐layered V‐MXene and selective, well‐controlled Ru atomic doping by ALD for the successful formation of Ru@DM‐V2CTX heterostructure. The advanced heterostructure formation, the mechanism, and the role of Ru have been comprehensively investigated by ultra‐high‐resolution transmission/scanning transmission electron microscopies coupled with next‐generation spherical aberration correction technology and fast, accurate elemental mapping quantifications, also by ultraviolet photoelectron spectroscopy. To the knowledge, this work is the first to use the novel, optimally processed V‐MXene over conventionally used Ti‐MXene and its surface‐internal structure engineering by Ru‐ALD process‐based temperature‐sensing devices function and operational demonstrations. The current work could potentially motivate the development of multifunctional, future, next‐generation, safe, personal healthcare electronic devices by the industrially scalable ALD technique.

This study investigates how to apply artificial intelligence for social innovations using two socio-political factors critical for a Behavioral Theory of the Firm (BTF) – uncertainty and conflict. The analysis leads to four approaches for applying artificial intelligence for social innovations such as the agent-based modeling, social entrepreneurship, stakeholder capital, and social contract approaches. The valuation of artificial intelligence in the projects is endogenously created while the social innovators evaluate their environments, goals, and technologies. The study offers step-by-step guidance to assess the performance of and to create implementation strategies for social innovation projects combined with artificial intelligence.

The present work demonstrates the effectiveness of a novel hybrid process comprising chemical vapor infiltration (CVI), electrophoretic deposition (EPD), and liquid silicon infiltration (LSI) techniques for the successful fabrication of low-porosity SiCf/SiC composites. For this purpose, fiber/matrix interphase dual coating layers of BN and SiC were coated onto SiC fabrics using CVI. A ceramic matrix consisting of SiC and carbon black nanoparticles was then infiltrated into the fine voids of the fabrics using EPD. Finally, LSI was performed to obtain dense microstructures with low porosities by filling the remaining small gaps and reacting Si with C to form SiC. Microstructural results observed by scanning electron microscopy revealed a dense structure with no damage to the fibers. The experimental density was found to be 2.62 g/cc, with an open porosity of 0.55. The room-temperature flexural strength was evaluated to be 111 MPa, and the composites displayed little fiber pull-out.

Abstract Background Alpha-1 antitrypsin (AAT) is a major serine protease inhibitor. AAT deficiency (AATD) is a genetic disorder characterized by early-onset severe emphysema. In well-selected AATD patients, therapy with plasma-derived AAT (pAAT), “augmentation therapy”, provides modest clinical improvement but is perceived as cumbersome with weekly intravenous infusions. Using mouse models of emphysema, we compared the effects of a recombinant AAT-IgG1 Fc-fusion protein (AAT-Fc), which is expected to have a longer half-life following infusion, to those of pAAT. Methods In an elastase model of emphysema, mice received a single intratracheal instillation of porcine pancreatic elastase (PPE) or human leucocyte elastase (hLE). AAT-Fc, pAAT, or vehicle was administered intraperitoneally 1 day prior to or 3 weeks following elastase instillation. Lung function and histology assessments were performed at 7 and 32 days after elastase instillation. In a cigarette smoke (CS) model of emphysema, mice were exposed to CS daily, 5 days a week, for 6 months and AAT-Fc, pAAT, or vehicle were administered every 10 days during the last 3 months of CS exposure. Assessments were performed 3 days after the last CS exposure. Immune responses to lung elastin peptide (EP) and the effects of AAT-Fc or pAAT treatment on dendritic cell (DC) function were determined ex vivo. Results Both elastase instillation and CS exposure triggered emphysema-like alveolar enlargement, increased lung compliance, and increased markers of inflammation compared to controls. Administration of AAT-Fc either prior to or following elastase instillation or during CS exposure provided greater protection than pAAT against alveolar enlargement, lung dysfunction, and airway inflammation. When challenged ex vivo with EP, spleen mononuclear cells from elastase-exposed mice exhibited dose-dependent production of IFNγ and IL-17, suggesting immune reactivity. In co-culture experiments with splenic CD4+ T cells isolated from elastase-exposed mice, AAT-Fc treatment prior to EP-priming of bone marrow-derived dendritic cells inhibited the production of IFNγ and IL-17. Conclusions Compared to pAAT, AAT-Fc more effectively prevented or attenuated elastase- and CS-induced models of emphysema. These effects were associated with immunomodulatory effects on DC activity. AAT-Fc may provide a therapeutic option to individuals with AATD- and CS-induced emphysema.

Abstract Background We investigated the feasibility of the clinical application of non‐invasive transthoracic echocardiography for diagnosis of pulmonary arterial hypertension induced by dasatinib (D‐PAH) in chronic myeloid leukemia (CML). Methods A total of 451 CML patients who were examined by 2D‐echocardiography at least once at baseline and/or during dasatinib therapy as frontline (n = 196) and subsequent line (n = 255) therapies were included in this study. D‐PAH was defined as right ventricular systolic pressure (RVSP) >40 mm Hg with relevant symptoms and the absence of other specific etiologies. Results A total of 847 echocardiographies were performed including at baseline (n = 255) and during dasatinib treatment (n = 592). During the median of 36.2 (0.1–181.8) months of dasatinib therapy, the level of RVSP gradually increased (Spearman's r = 0.2819, p 40 mm Hg without (asymptomatic, n = 27, 48.2%) or with symptoms (D‐PAH, n = 29, 51.8%). All asymptomatic patients maintained dasatinib therapy without further symptoms and the D‐PAH patients ultimately switched to other tyrosine kinase inhibitors. After dasatinib discontinuation, 13 (45%) and 15 (52%) patients showed RVSP normalization and gradual decrease, respectively. Conclusions Our large cohort study demonstrated that the gradual increment of RVSP might be induced by dasatinib and non‐invasive echocardiography can be fast way for early diagnosis as well as for monitoring of D‐PAH.

Purpose – The capital asset pricing model has failed to explain the effect of systematic risk (referred to as beta) on actual stock market returns. Accordingly, this study analyzes daily returns by splitting it into overnight and daytime returns. The study analysis empirically confirms a positive relationship between overnight returns and beta and a negative relation between daytime returns and beta. Furthermore, this paper aims to determine that empirical results are mostly the same with three different beta calculations, namely, daily, overnight and daytime returns. The study concludes that beta on overnight returns has the strongest explanatory power and is statistically significant.

WD40-repeat (WDR)-containing proteins constitute an evolutionarily conserved large protein family with a broad range of biological functions. In human proteome, WDR makes up one of the most abundant protein-protein interaction domains. Members of the WDR protein family play important roles in nearly all major cellular signalling pathways. Mutations of WDR proteins have been associated with various human pathologies including neurological disorders, cancer, obesity, ciliopathies and endocrine disorders. This review provides an updated overview of the biological functions of WDR proteins and their mutations found in congenital disorders. We also highlight the significant role of WDR proteins in ciliopathies and endocrine disorders. The new insights may help develop therapeutic approaches targeting WDR motifs.

How co-receptors Gas1 and Boc interact with Ptch1/2 receptors and regulate Hh signalling is unclear. Here, the authors demonstrate that the spatiotemporal expression of Gas1 and Boc determines how Hh signalling affects the dynamic migration of murine primordial germ cells.

The vehicle front-end module (FEM) is an integrated system in which major modules are assembled in the front of the vehicle. Among the FEM components, a carrier occupies the largest volume and weight. In recent years, the requirements of a carrier are increasing due to the diversification of vehicle size, enlargement of headlight, and so on. So, recent requirements are difficult to satisfy with the existing design. Therefore, this study was attempted to solve the current problems by applying only plastic, not the existing hybrid type, to the most important Member-radiator Support Upper (MRSU) of the carrier. As a process, topology optimization was performed using Altair’s Optistruct, thereby implementing a new concept of MRSU. In addition, the strength analysis was conducted using ABAQUS of Simulia. An initial model and an optimized model were compared and verified to determine the validity of optimization. After that, a prototype of carrier was manufactured and the final verification was conducted through HLR test. As a result, the strength and weight of the carrier were improved by about 24% and 15% respectively. In addition, the waste-generating process was improved, resulting in a development time reduction of approximately 32%.

The pharmacological potential of industrial hemp (Cannabis sativa) has been widely studied. However, the majority of studies have focused on cannabidiol, isolated from the inflorescence and leaf of the plant. In the present study, we evaluated the anti-diabetic potential of hemp root water (HWE) and ethanol extracts (HEE) in streptozotocin (STZ)-induced insulin-deficient diabetic mice. The administration of HWE and HEE ameliorated hyperglycemia and improved glucose homeostasis and islet function in STZ-treated mice (p < 0.05). HWE and HEE suppressed β-cell apoptosis and cytokine-induced inflammatory signaling in the pancreas (p < 0.05). Moreover, HWE and HEE normalized insulin-signaling defects in skeletal muscles and apoptotic response in the liver and kidney induced by STZ (p < 0.05). Gas chromatography-mass spectrometry analysis of HWE and HEE showed possible active compounds which might be responsible for the observed anti-diabetic potential. These findings indicate the possible mechanisms by which hemp root extracts protect mice against insulin-deficient diabetes, and support the need for further studies geared towards the application of hemp root as a novel bioactive material.

Abstract Ir is one of the most efficient oxygen evolution reaction (OER) catalysts; however, it is also one of the rarest and most expensive elements. Therefore, it is highly desirable to develop Ir catalysts with nanostructures that reduce Ir consumption by maximizing the surface‐to‐volume ratio without limiting the mass transport of reactants and products of reactions. Ir OER catalysts on a template that consisted of porous nanotubes (PNTs) based on Ni are fabricated. The Ir/Ni PNTs offer multiple benefits, including high catalytic performance (potential of 1.500 V vs. reversible hydrogen electrode (RHE) at an operating current density of 10 mA cm−2 and Tafel slope of 44.34 mV decade−1), minimal use of Ir (mass activity of 3273 A g−1 at 1.53 V vs RHE), and facile mass transport through the NT‐sidewall pores (stable operation for more than 10 h). The Ir/Ni PNTs are also applied to a tandem device, consisting of a Cu(In,Ga)Se2‐based photocathode and halide perovskite photovoltaic cell, for unassisted water splitting. A solar‐to‐hydrogen conversion efficiency that exceeded 10% is also demonstrated, which is nearly 1% point greater than when a planar Ir film is used as the anode instead of Ir/Ni PNTs.

Abstract Background The Multicenter Orthopaedic Outcomes Network (MOON) group recently reported that medial meniscus (MM) repairs are associated with more frequent re-operations when compared to lateral meniscus (LM) repairs. The purpose of this study was to compare the meniscal healing and the incidence of subsequent re-operation of medial and lateral meniscal tears that occurred concurrently with anterior cruciate ligament (ACL) injuries. Methods We retrospectively reviewed patients who underwent second-look arthroscopy after primary ACL reconstruction (ACLR) between June 2005 to December 2016. The healing of meniscal tears following repair or left in situ, and re-tear following partial meniscectomy, were evaluated via second-look arthroscopy and compared between medial and lateral meniscus. Moreover, the incidence of subsequent meniscal re-operation after the index ACLR were investigated and compared between medial and lateral meniscus. Subsequent meniscal re-operation was performed in cases of the following three symptomatic meniscus tears: re-tears at the meniscectomy site; new tears; and failed healing of repaired or left in situ meniscus. Results There were 148 meniscal tears in 121 patients at index ACLR. There were 62 MM tears, 38 LM tears, and 24 bilateral meniscus tears. At second-look arthroscopy, the “successful healing” rate for tears following repair was higher in LM tears (91.2%) compared to MM tears (80.0%), although it was not statistically significant (p > 0.05). No significant differences were observed in the healing of left in situ tears or re-tear of meniscectomy site between medial and lateral meniscus. Patients with MM tears combined with ACL injuries had a higher incidence of subsequent meniscal re-operation compared to patients with LM tears (25.6% vs 16.1%, p = 0.025). Conclusions There was a trend for the successful healing rate to be higher in LM repairs than MM repairs. Subsequent meniscal re-operations after ACLR were more frequent in patients with medial meniscal tears concurrently with ACL injuries in comparison to patients with lateral meniscal tears. Level of study Level IV, retrospective case series.

Purpose This study attempts to evaluate the skeletal maturation patterns of the triradiate cartilage (TRC) and the posterior acetabular wall (PA), which can be easily assessed on body computerized tomography (CT). It also examines the effect of gender and age on ossification of both TRC and PA. Materials and Methods This retrospective study included a total of 1324 CT scans for children between the ages of 6 and 16 years. Depending on the extent of ossification in each right or left aspect, determined by the consensus of two observers, the TRC and PA scans were categorized into Grades 4 and 3, respectively. Results The TRC for boys began to ossify at age 10 and closed completely at 14, while the PA for boys started ossification at age 11 and entirely fused at 13. The ages of ossification center appearance and complete fusion in both TRC and PA for girls were exactly two years earlier than boys. The TRC fused within one year after the closure of the PA. Conclusion The appearance and closure of the TRC and PA ossification centers show predictable patterns of development, appearance and merger earlier in females than in males. The suggestion is that development and morphogenesis of both TRC and PA ossification centers can be adequately assessed by using 3-dimensional body CT.

Introduction Coronary CT angiography (CCTA) is widely used for non-invasive coronary artery evaluation, but it is limited in identifying the nature of functional characteristics that cause ischaemia. Recent computational fluid dynamic (CFD) techniques applied to CCTA images permit non-invasive computation of fractional flow reserve (FFR), a measure of lesion-specific ischaemia. However, this technology has limitations, such as long computational time and the need for expensive equipment, which hinder widespread use.Methods and analysis This study is a prospective, multicentre, comparative and confirmatory trial designed to evaluate the diagnostic performance of HeartMedi V.1.0, a novel CT-derived FFR measurement for the detection of haemodynamically significant coronary artery stenoses identified by CCTA, based on invasive FFR as a reference standard. The invasive FFR values ≤0.80 will be considered haemodynamically significant. The study will enrol 184 patients who underwent CCTA, invasive coronary angiography and invasive FFR. Computational FFR (c-FFR) will be analysed by CFD techniques using a lumped parameter model based on vessel length method. Blinded core laboratory interpretation will be performed for CCTA, invasive coronary angiography, invasive FFR and c-FFR. The primary objective of the study is to compare the area under the receiver–operator characteristic curve between c-FFR and CCTA to non-invasively detect the presence of haemodynamically significant coronary stenosis. The secondary endpoints include diagnostic accuracy, sensitivity, specificity, positive predictive value, negative predictive value and correlation of c-FFR with invasive FFR.Ethics and dissemination The study has ethic approval from the ethics committee of Seoul National University Bundang Hospital (E-1709/420-001) and informed consent will be obtained for all enrolled patients. The result will be published in a peer-reviewed journal.Trial registration number KCT0002725; Pre-results.

The unique ability of retroviruses to integrate genes into host genomes is of great value for long-term expression in gene therapy, but only when integrations occur at safe genomic sites. To reap the benefit of using retroviruses without severe detrimental effects, we developed several murine leukemia virus (MLV)-based gammaretroviral vectors with safer integration patterns by perturbing the structure of the integrase via insertion of DNA-binding zinc-finger domains (ZFDs) into an internal position of the enzyme. ZFD insertion significantly reduced the inherent, strong MLV integration preference for genomic regions near transcriptional start sites (TSSs), which are the most dangerous spots. The altered retroviral integration pattern was related to increased formation of residual primer-binding site sequences at the 3′ end of proviruses. Several ZFD insertion mutants showed lower frequencies of integrations into the TSS genome regions when having the residual primer-binding site sequences in the proviruses. Our findings not only can extend the use of retroviruses in biomedical applications, but also provide a glimpse into the mechanisms underlying retroviral integration. Keywords: gammaretroviral vectors, DNA-binding protein domain, integrase, primer-binding site, transcriptional start sites

Supercapacitors (SCs) have attracted attention as an important energy source for various applications owing to their high power outputs and outstanding energy densities. The electrochemical performance of an SC device is predominantly determined by electrode materials, and thus, the selection and synthesis of the materials are crucial. Metal oxides (MOs) and their composites are the most widely used pseudocapacitive SC electrode materials. The basic requirements for fabricating high-performance SC electrodes include synthesizing and/or chemically modifying unique conducting nanostructures, optimizing a heterostructure morphology, and generating large-surface-area electroactive sites, all of which predominantly rely on various techniques used for synthesizing MO materials and fabricating MO- and MO-composite-based SC electrodes. Therefore, an SC’s background and critical aspects, the challenges associated with the predominant synthesis techniques (including hydrothermal and microwave-assisted syntheses and chemical-bath and atomic-layer depositions), and resulting electrode electrochemical performances should be summarized in a convenient, accessible report to accelerate the development of materials for industrial SC applications. Therefore, we reviewed the most pertinent studies on these synthesis techniques to provide insight into the most recent advances in synthesizing MOs and fabricating their composite-based SC electrodes as well as to propose research directions for developing MO-based electrodes for applications to next-generation SCs.

Cancer immunotherapy: Improving animal models Improvements to mouse models for cancer immunotherapy could enhance the precision of new drugs. Immunotherapy trials require genetically modified animal models, including ‘humanized’ mice with a functioning human immune system, and patient-derived xenograft (PDX) mice, in which cells from patients’ tumors are implanted into immunodeficient mice. Charles Lee at the Jackson Laboratory for Genomic Medicine in Farmington, USA, Yeun-Jun Chung at the Catholic University of Korea in Seoul, and co-workers reviewed developments in both PDX and humanized-PDX mouse models for immunotherapy trials. PDX models improve the chances of finding novel biomarkers for drug development. However, humanized PDX mouse models will allow researchers to study diverse cancers in tumour and immune environments as close as possible to those of humans.

Cytokines such as TNF and IFN-γ are important for immunity against hepatitis B virus (HBV). Here the authors show that interleukin-32 gamma (IL-32γ) acts downstream of TNF and IFN-γ as an intracellular effector, and that IL-32γ negatively regulates host factors contributing to HBV transcription to promote HBV clearance.

Magnesium oxysulfate (MOS) whisker is considered as a promising inorganic material recently attracting a great attention for being used as a reinforcing filler for polymer composites due to high aspect ratio and extremely-low bulk density. In this study, the MOS was treated with 3-methacryloyloxypropyl-trimethoxy silane (MPS) via sol-gel condensation reactions, which successfully allowed melt mixing with polypropylene (PP) up to 30 wt% of MOS. The tensile strength at yield and modulus of the MOS/PP composites were substantially increased by 50.8% and 362%, respectively, when compared with the pristine PP. As a novel finding, the flame retardancy of MOS was proved by identifying water evolution at elevated temperatures giving out 9 wt% of water in 250–320 °C and 14 wt% in 350–420 °C in two steps. This work demonstrated that the MOS could be an excellent filler for PP not only increasing the mechanical properties in a great extent but also imposing flame retarding capability. Keywords: Magnesium oxysulfate, Surface modification, Mechanical properties, Flame retardant

Mixed metal sulfides exhibit outstanding electrochemical performance compared to single metal sulfides and mixed metal oxides because of their richer redox reactions and high electronic conductivity. In the present study, Zn-Co-S nanostrip cluster arrays were formed from ZnCo2O4 grown on Ni foam by an anion exchange reaction using a two-step hydrothermal process. Morphological characterization confirmed that the Zn-Co-S nanostrip cluster arrays had grown homogeneously on the skeleton of the 3D Ni foam. The length of the nanostrip was approximately 8 µm, and the width ranged from 600 to 800 nm. The Ni foam-supported Zn-Co-S nanostrip cluster arrays were assessed directly for electrochemical supercapacitor applications. Compared to ZnCo2O4, the Zn-Co-S electrode exhibited a three-fold higher specific capacity of 830 C g−1 at a specific current of 2.0 A g−1. The higher polarizability, lower electro-negativity, and larger size of the S2− ion played an important role in substituting oxygen with sulfur, which enhanced the performance. The Zn-Co-S//AC hybrid device delivered a maximum specific energy of 19.0 Wh kg−1 at a specific power of 514 W kg−1. The remarkable performance of Zn-Co-S nanostrip cluster arrays highlights their potential as a positive electrode for hybrid supercapacitor applications.

The oxygen transport membrane (OTM) is a high-density ion-conducting ceramic membrane that selectively transfers oxygen ions and electrons through the pressure differential across its layers. It can operate at more than 800 °C and serves as an economical method for gas separation. However, it is difficult to predict the material properties of the OTM through experiments or analyses because its structure contains pores and depends on the characteristics of the ceramic composite. In addition, the transmittance of porous ceramic materials fluctuates strongly owing to their irregular structure and arbitrary shape, making it difficult to design such materials using conventional methods. This study analyzes the structural weakness of an OTM using CAE software (ANSYS Inc., Pittsburgh, PA, USA). To enhance the structural strength, a structurally optimized design of the OTM was proposed by identifying the relevant geometric parameters.

The orphan nuclear receptor 4A1 (NR4A1) is overexpressed in pancreatic cancer and exhibits pro-oncogenic activity, and NR4A1 silencing and treatment with its inactivators has been shown to inhibit pancreatic cancer cells and tumor growth. In this study, we identified broussochalcone A (BCA) as a new NR4A1 inhibitor and demonstrated that BCA inhibits cell growth partly by inducing NR4A1-mediated apoptotic pathways in human pancreatic cancer cells. BCA downregulated specificity protein 1 (Sp1)-mediated expression of an anti-apoptotic protein, survivin, and activated the endoplasmic reticulum (ER) stress-mediated apoptotic pathway. These results suggest that NR4A1 inactivation contributes to the anticancer effects of BCA, and that BCA represents a potential anticancer agent targeting NR4A1 that is overexpressed in many types of human cancers.

A commercial aircraft, departing from Seoul to Jeju Island in South Korea, encountered a convectively induced turbulence (CIT) at about z = 2.2 km near Seoul on 28 October 2018. At this time, the observed radar reflectivity showed that the convective band with cloud tops of z = 6–7 km passed the CIT region with high values of spectral width (SW; larger than 4 m s–1). Using the 1 Hz wind data recorded by the aircraft, we estimated an objective intensity of the CIT as a cube root of eddy dissipation rate (EDR) based on the inertial range technique, which was about 0.33–0.37 m2/3 s−1. Radar-based EDR was also derived by lognormal mapping technique (LMT), showing that the EDR was about 0.3–0.35 m2/3 s−1 near the CIT location, which is consistent with in situ EDR. In addition, a feasibility of the CIT forecast was tested using the weather and research forecast (WRF) model with a 3 km horizontal grid spacing. The model accurately reproduced the convective band passing the CIT event with an hour delay, which allows the use of two methods to calculate EDR: The first is using both the sub-grid and resolved turbulent kinetic energy to infer the EDR; the second is using the LMT for converting absolute vertical velocity (and its combination with the Richardson number) to EDR-scale. As a result, we found that the model-based EDRs were about 0.3–0.4 m2/3 s−1 near the CIT event, which is consistent with the estimated EDRs from both aircraft and radar observations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Breast cancer brain metastases remain largely incurable. Although several mouse models have been developed to investigate the genes and mechanisms regulating breast cancer brain metastasis, these models often lack clinical relevance since they require the use of immunocompromised mice and/or are poorly metastatic to brain from the mammary gland. We describe the development and characterisation of an aggressive brain metastatic variant of the 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. As seen by immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple-negative phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate across a brain-derived endothelial monolayer and greater invasive response to brain-derived soluble factors compared to 4T1 cells. These properties are likely to contribute to the brain selectivity of 4T1Br4 tumours. Expression profiling and gene set enrichment analyses demonstrate the clinical relevance of the 4T1Br4 model at the transcriptomic level. Pathway analyses implicate tumour-intrinsic immune regulation and vascular interactions in successful brain colonisation, revealing potential therapeutic targets. Evaluation of two histone deacetylase inhibitors, SB939 and 1179.4b, shows partial efficacy against 4T1Br4 metastasis to brain and other sites in vivo, and potent radio-sensitising properties in vitro. The 4T1Br4 model provides a clinically relevant tool for mechanistic studies and to evaluate novel therapies against brain metastasis. This article has an associated First Person interview with Soo-Hyun Kim, joint first author of the paper.

The proper development and coordination of the hypothalamic-pituitary-gonadal (HPG) axis are essential for normal reproductive competence. The key factor that regulates the function of the HPG axis is gonadotrophin-releasing hormone (GnRH). Timely release of GnRH is critical for the onset of puberty and subsequent sexual maturation. Misregulation in this system can result in delayed or absent puberty and infertility. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are genetic disorders that are rooted in a GnRH deficiency but often accompanied by a variety of non-reproductive phenotypes such as the loss of the sense of smell and defects of the skeleton, eye, ear, kidney, and heart. Recent progress in DNA sequencing technology has produced a wealth of information regarding the genetic makeup of CHH and KS patients and revealed the resilient yet complex nature of the human reproductive neuroendocrine system. Further research on the molecular basis of the disease and the diverse signal pathways involved will aid in improving the diagnosis, treatment, and management of CHH and KS patients as well as in developing more precise genetic screening and counseling regime.

A hindrance to the practical use of sodium-ion batteries is the lack of adequate anode materials. By utilizing the co-intercalation reaction, graphite, which is the most common anode material of lithium-ion batteries, was used for storing sodium ion. However, its performance, such as reversible capacity and coulombic efficiency, remains unsatisfactory for practical needs. Therefore, to overcome these drawbacks, a new carbon material was synthesized so that co-intercalation could occur efficiently. This carbon material has the same morphology as carbon black; that is, it has a wide pathway due to a turbostratic structure, and a short pathway due to small primary particles that allows the co-intercalation reaction to occur efficiently. Additionally, due to the numerous voids present in the inner amorphous structure, the sodium storage capacity was greatly increased. Furthermore, owing to the coarse co-intercalation reaction due to the surface pore structure, the formation of solid-electrolyte interphase was greatly suppressed and the first cycle coulombic efficiency reached 80%. This study shows that the carbon material alone can be used to design good electrode materials for sodium-ion batteries without the use of next-generation materials.

The aim of the Korean Imatinib Discontinuation Study was to identify predictors for safe and successful imatinib discontinuation. A total of 90 patients with a follow-up of ≥12 months were analyzed. After a median follow-up of 26.6 months after imatinib discontinuation, 37 patients lost the major molecular response. The probability of sustained major molecular response at 12 months and 24 months was 62.2% and 58.5%, respectively. All 37 patients who lost major molecular response were retreated with imatinib therapy for a median of 16.9 months, and all achieved major molecular response again at a median of 3.9 months after resuming imatinib therapy. We observed newly developed or worsened musculoskeletal pain and pruritus in 27 (30%) patients after imatinib discontinuation. Imatinib withdrawal syndrome was associated with a higher probability of sustained major molecular response (P=0.003) and showed a trend for a longer time to major molecular response loss (P=0.098). Positivity (defined as ≥ 17 positive chambers) of digital polymerase chain reaction at screening and longer imatinib duration before imatinib discontinuation were associated with a higher probability of sustained major molecular response. Our data demonstrated that the occurrence of imatinib withdrawal syndrome after imatinib discontinuation and longer duration of imatinib were associated with a lower rate of molecular relapse. In addition, minimal residual leukemia measured by digital polymerase chain reaction had a trend for a higher molecular relapse. (Trial registered at ClinicalTrials.gov: NCT01564836).

Aquaporins (AQPs) have previously been associated with increased expression in solid tumors. However, its expression in hematologic malignancies including CML has not been described yet. Here, we report the expression of AQP5 in CML cells by RT-PCR and immunohistochemistry. While normal bone marrow biopsy samples (n = 5) showed no expression of AQP5, 32% of CML patient samples (n = 41) demonstrated AQP5 expression. In addition, AQP5 expression level increased with the emergence of imatinib mesylate resistance in paired samples (p = 0.047). We have found that the overexpression of AQP5 in K562 cells resulted in increased cell proliferation. In addition, small interfering RNA (siRNA) targeting AQP5 reduced the cell proliferation rate in both K562 and LAMA84 CML cells. Moreover, by immunoblotting and flow cytometry, we show that phosphorylation of BCR-ABL1 is increased in AQP5-overexpressing CML cells and decreased in AQP5 siRNA-treated CML cells. Interestingly, caspase9 activity increased in AQP5 siRNA-treated cells. Finally, FISH showed no evidence of AQP5 gene amplification in CML from bone marrow. In summary, we report for the first time that AQP5 is overexpressed in CML cells and plays a role in promoting cell proliferation and inhibiting apoptosis. Furthermore, our findings may provide the basis for a novel CML therapy targeting AQP5.

Interleukin (IL)-32 is a newly described proinflammatory cytokine that seems likely to play a role in inflammation and host defense. Little is known about the regulation of IL-32 production by primary cells of the immune system.In the present study, freshly obtained human peripheral blood mononuclear cells were stimulated with different Toll-like receptor (TLR) agonists, and gene expression and synthesis of IL-32 was determined. We demonstrate that the TLR4 agonist lipopolysaccharide induces moderate (4-fold) production of IL-32, whereas agonists of TLR2, TLR3, TLR5, or TLR9, each of which strongly induced tumor necrosis factor alpha and IL-6, did not stimulate IL-32 production. However, the greatest amount of IL-32 was induced by the mycobacteria Mycobacterium tuberculosis and M. bovis BCG (20-fold over unstimulated cells). IL-32-induced synthesis by either lipopolysaccharide or mycobacteria remains entirely cell-associated in monocytes; moreover, steady-state mRNA levels are present in unstimulated monocytes without translation into IL-32 protein, similar to other cytokines lacking a signal peptide. IL-32 production induced by M. tuberculosis is dependent on endogenous interferon-gamma (IFNgamma); endogenous IFNgamma is, in turn, dependent on M. tuberculosis-induced IL-18 via caspase-1.In conclusion, IL-32 is a cell-associated proinflammatory cytokine, which is specifically stimulated by mycobacteria through a caspase-1- and IL-18-dependent production of IFNgamma.

Purpose: Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease characterized by the loss of motor neurons in the spinal cord and brainstem, leading to muscle atrophy and weakness. To understand the diagnostic process of Korean patients with SMA, we analyzed their clinical characteristics and challenges. Materials and Methods: We conducted a retrospective study of 38 patients with SMA (9 type II and 29 type III) between January 2000 and September 2023. Clinical, laboratory, and genetic data were reviewed. Results: The median ages at symptom onset and diagnosis were 3.0 years [interquartile range (IQR): 1.0-7.3 years] and 25.0 years (IQR: 10.5-37.3 years), respectively. The median diagnostic delay was 19.6 years (IQR: 6.4-31.0 years). A significantly longer delay was observed in SMA type III patients (median: 21.0 years, IQR: 11.0-31.0 years) compared to SMA type II patients (median: 3.0 years, IQR: 0.9-21.0 years) (p=0.021). No significant difference was observed in the number of clinic visits before diagnosis between patients with SMA type II (median: 2.0, IQR: 1.0-4.5) and those with type III (median: 2.0, IQR: 2.0-6.0, p=0.282). The number of clinic visits before diagnosis showed no significant association with the age at symptom onset and diagnosis (p=0.998 and 0.291, respectively). Conclusion: Our investigation is the first examination of the diagnostic journey of Korean patients with SMA. As treatments for SMA progress, the significance of an accurate diagnosis has increased, highlighting the importance of reviewing the diagnostic advancements made thus far. [ABSTRACT FROM AUTHOR]