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Abstract Patients with stroke may develop hyperperfusion after a successful endovascular thrombectomy (EVT). However, the relationship between post-EVT hyperperfusion and clinical outcomes remains unclear and requires further clarification. We reviewed consecutive patients with anterior circulation occlusion who were successfully recanalized with EVT. Based on post-EVT arterial spin-labeling images, hyperperfusion was categorized as follows: global hyperperfusion (GHP), increased cerebral blood flow (CBF) in ≥ 50% of the culprit vessel territory; focal hyperperfusion (FHP), increased CBF in

This study investigates the impact of atmospheres (Ar and N2) on Fe-12Cr-6Al alloy fabricated using laser powder bed fusion (L-PBF) in terms of melt pool shape/size, microstructure, precipitate characteristics, and mechanical properties. The sample built in the N2 atmosphere exhibited lower porosity, wider melt pools, and no Al2O3 agglomeration. Oxygen content decreased from 0.012 to 0.0045 (wt.%), and nitrogen content increased from 0.013 to 0.02 (wt.%). The Ar-printed sample had a yield strength (YS) of 232 ± 15 MPa, ultimate tensile strength (UTS) of 286 ± 10 MPa, and total elongation (TE) of 6.4 ± 1.3 %, while the N2-printed sample showed significant improvements of the mechanical properties: YS of 315 ± 11 MPa, UTS of 401 ± 11 MPa, and TE of 7.8 ± 1.1 %. Therefore, N2 might be considered to replace Ar as a cost-effective shielding gas for FeCrAl alloys, with improved properties.

BackgroundChronic rhinosinusitis (CRS) is an inflammatory disease affecting more than 10% of the global adult population. It is classified into Th1, Th2, and Th17 endotypes and eosinophilic and non-eosinophilic types. Th2-based inflammation and eosinophilic CRS (ECRS) are associated with tissue remodeling and fibrinolytic system impairment.ObjectiveTo elucidate the role of eosinophils in inducing fibrin deposition in CRS nasal polyp tissues and explore potential regulatory mechanisms.MethodsWe analyzed the expression of genes related to the serpin family and fibrinolytic system using Gene Expression Omnibus and Next-generation sequencing data. Differentially expression genes (DEGs) analysis was used to compare control and nasal polyp tissues, followed by KEGG and Gene ontology (GO) analysis. We measured the expression and correlation of plasminogen activator-1 (PAI-1), tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), and urokinase plasminogen activator surface receptor (u-PAR) in CRS tissues, and evaluated the effect of eosinophils on the fibrinolytic system using a cytokine array and co-culture.ResultsNasal polyp tissues showed upregulated PAI-1, u-PA, and u-PAR expression and downregulated t-PA expression. Fibrinolytic system-related genes positively correlated with Th2 cytokines, except for t-PA. Eosinophil-derived Chitinase-3-like protein 1 (CHI3L1) increased PAI-1 expression and decreased t-PA levels in fibroblasts and epithelial cells. The inhibition of CHI3L1 suppresses these alterations.ConclusionCHI3L1 contributes to fibrin deposition by impairing the fibrinolytic system during nasal polyp formation. The regulation of CHI3L1 expression may inhibit fibrin deposition and edema in ECRS, presenting a potential treatment for this condition.

Immune-modulatory effects in obese-diabetes (db/db) mice were observed to understand the possible mechanism(s) of ephedrine-induced unfavorable responses. The ephedrine doses were selected based on the FDA report (NTP Tech Rep Ser NO 307; CAS# 134-72-5), which showed the non-toxic dose for B6C3F1 mice. In db/db mice, higher doses (6 and 12 mg/mouse) of ephedrine significantly harmed the liver and lung morphology, including fatty liver with multiple blood vessel engorgement, alveolar wall thickening, and inflammatory response in the lung. The immune micro-environment of db/db mice was an inflammatory state with suppressed adaptive cellular immunity. After the administration of ephedrine, significant deterioration of NK activity was observed with lowered gene transcription of klrk1 encoding NKG2D, and of ccl8, a NK cell targeting chemokine. Suppressed cellular immunity in db/db mice was lowered ever further by single ephedrine treatment, as was evidenced by mitogen-induced T or B cell proliferations. These observations demonstrate that at the non-toxic doses in normal B6C3F1 mice, ephedrine clearly suppressed systemic immunity of db/db mice. The data suggest that the immune micro-environment of obese individuals is fragile and susceptible to ephedrine-related pathologic response, and this may be a prelude to the induction of obesity-related secondary immunological disorders.

This study endeavors to investigate the feasibility of in situ synthesis of nitrides and oxides within Fe-12Cr-6Al alloys through precise modulation of reactive gas atmosphere during the Laser-Powder Bed Fusion process. A focused study on elucidating the effects of critical process parameters, such as laser power, scanning speed, and hatch distance, was undertaken to discern their impact on the material's microstructure, oxygen/nitrogen content, and hardness. Synthesis of nano-sized AlN and Al2O3 precipitates within the Fe-12Cr-6Al matrix was achieved when nitrogen was used for a process gas. A rise in laser power from 120 W to 200 W, coupled with a reduction in scanning speed from 1200 mm/s to 400 mm/s, resulted in decreased porosity and an increase in grain size. Additionally, all printed samples showed lower oxygen content compared to the initial powder, while nitrogen ratios were notably higher. A marginal increase of the Vickers hardness value, from 240 ± 4.5 to 266 ± 3 HV, was observed as the laser power increased and the scanning speed decreased. The hardness values were higher than those obtained from different production methods with identical compositions. These compelling results suggest a positive impact of nitride precipitates and oxide precipitates to improve hardness values.

Background While Programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) blockade is a potent antitumor treatment strategy, it is effective in only limited subsets of patients with cancer, emphasizing the need for the identification of additional immune checkpoints. Butyrophilin 1A1 (BTN1A1) has been reported to exhibit potential immunoregulatory activity, but its ability to function as an immune checkpoint remains to be systematically assessed, and the mechanisms underlying such activity have yet to be characterized.Methods BTN1A1 expression was evaluated in primary tumor tissue samples, and its ability to suppress T-cell activation and T cell-dependent tumor clearance was examined. The relationship between BTN1A1 and PD-L1 expression was further characterized, followed by the development of a BTN1A1-specific antibody that was administered to tumor-bearing mice to test the amenability of this target to immune checkpoint inhibition.Results BTN1A1 was confirmed to suppress T-cell activation in vitro and in vivo. Robust BTN1A1 expression was detected in a range of solid tumor tissue samples, and BTN1A1 expression was mutually exclusive with that of PD-L1 as a consequence of its inhibition of Janus-activated kinase/signal transducer and activator of transcription signaling-induced PD-L1 upregulation. Antibody-mediated BTN1A1 blockade suppressed tumor growth and enhanced immune cell infiltration in syngeneic tumor-bearing mice.Conclusion Together, these results confirm that the potential of BTN1A1 is a bona fide immune checkpoint and a viable immunotherapeutic target for the treatment of individuals with anti-PD-1/PD-L1 refractory or resistant disease, opening new avenues to improving survival outcomes for patients with a range of cancers.

This study assesses the early effectiveness of esketamine nasal spray (ESK) in adults with treatment-resistant depression (TRD) 1 day after the first administration, as monitored through self-assessment via the mobile application, Esketamine Continuing Assessment for Relapse Prevention (EsCARe). In this multi-center, open-label, single-arm study, adults aged 18–65 years diagnosed with TRD after failing at least two antidepressant therapies were enrolled from five tertiary hospitals in South Korea. During the induction period, participants self-administered ESK twice weekly and used the EsCARe app daily to record mood, sleep, and somatic symptoms. Key clinical assessments, the Patient Health Questionnaire-9 (PHQ-9), the Hamilton Depression Rating Scale (HAMD), and the Generalized Anxiety Disorder Scale (GAD-7), were measured at baseline and at weeks 2 and 4. The reliability and validity of EsCARe was assessed. The treatment results indicated significant improvements in depressive and anxiety symptoms, with notable reductions in the PHQ-9 and the GAD-7 by week 2, and the HAMD by week 4. The EsCARe app reliably and validly monitored depressive symptoms and demonstrated a significant reduction in depressive symptoms 1 day after the first administration of ESK. Using ESK, complemented by mobile self-monitoring, effectively reduces the symptoms of TRD early in the treatment course. Integrating mobile health technology into the therapeutic regimen highlights a significant advancement in managing TRD, offering patients and clinicians immediate feedback on treatment efficacy.

This work investigates the stability conditions for linear systems with time-varying delays via an augmented Lyapunov–Krasovskii functional (LKF). Two types of augmented LKFs with cross terms in integrals are suggested to improve the stability conditions for interval time-varying linear systems. In this work, the compositions of the LKFs are considered to enhance the feasible region of the stability criterion for linear systems. Mathematical tools such as Wirtinger-based integral inequality (WBII), zero equalities, reciprocally convex approach, and Finsler’s lemma are utilized to solve the problem of stability criteria. Two sufficient conditions are derived to guarantee the asymptotic stability of the systems using linear matrix inequality (LMI). First, asymptotic stability criteria are induced by constructing the new augmented LKFs in Theorem 1. Then, simplified LKFs in Corollary 1 are proposed to show the effectiveness of Theorem 1. Second, asymmetric LKFs are shown to reduce the conservatism and the number of decision variables in Theorem 2. Finally, the advantages of the proposed criteria are verified by comparing maximum delay bounds in four examples. Four numerical examples show that the proposed Theorems 1 and 2 obtain less conservative results than existing outcomes. Particularly, Example 2 shows that the asymmetric LKF methods of Theorem 2 can provide larger delay bounds and fewer decision variables than Theorem 1 in some specific systems.

Objective Pork belly is a cut of meat with high worldwide demand. However, although the belly is comprised of multiple muscles and fat, unlike the loin muscle, research on their genetic parameters has yet to focus on a representative cut. To use swine breeding, it is necessary to estimate heritability against pork belly traits. Moreover, estimating genetic correlations is needed to identify genetic relationship among the traditional carcass and meat quality traits. This study sought to estimate the heritability of the carcass, belly, and their component traits, as well as the genetic correlations among them, to confirm whether these traits can be improved. Methods A total of 543 Yorkshire pigs (406 castrated males and 137 females) from 49 sires and 244 dam were used in this study. To estimate genetic parameters, a total of 12 traits such as lean meat production ability, meat quality and pork belly traits were chosen. The heritabilities were estimated by using genome-wide efficient mixed model association software. The statistical model was selected so that farm, carcass weight, sex, and slaughter season were fixed effects. In addition, its genetic parameters were calculated via MTG2 software. Results The heritability estimates for the 7th belly slice along the whole plate and its components were low to moderate (0.07±0.07 to 0.33±0.07). Moreover, the genetic correlations among the carcass and belly traits were moderate to high (0.28±0.20 to 0.99±0.31). Particularly, the rectus abdominis muscle exhibited a high absolute genetic correlation with the belly and meat quality (0.73±52 to 0.93±0.43). Conclusion A moderate to high correlation coefficient was obtained based on the genetic parameters. The belly could be genetically improved to contain a larger proportion of muscle regardless of lean meat production ability.

Objectives In 2021, the effectiveness of the COVID-19 vaccine was analyzed among people living in the Honam region (Gwangju, Jeollanam-do, Jeollabuk-do, and Jeju) of the Republic of Korea. And we investigated changes in the dominant virus strain. Methods This study used the data provided by the Korean Ministry of the Interior and Safety for individuals ≥12 years old in the Honam region, and the Integrated Disease and Health Management System of the Korea Centers for Disease Control and Prevention for COVID-19-vaccinated individuals as of December 31, 2021. Statistical analyzes were performed using IBM SPSS ver. 23.0. The occurrence of confirmed cases by vaccination status, the relative risk, and vaccine effectiveness by vaccine type were calculated. Results In 2021, the COVID-19 vaccination rate in Honam was 88.6%. The overall vaccine effectiveness (after 2 and 3 doses) was 98.7% (p98%, and the effect among persons who received 2 doses was >90% regardless of the vaccine type. Although vaccine effectiveness decreased because of reduced antibody levels over time (as observed in breakthrough infections), receiving a booster dose restored the neutralizing antibody levels.

Abstract Ultra-flexible organic photovoltaics (OPVs) are promising candidates for next-generation power sources owing to their low weight, transparency, and flexibility. However, obtaining ultra-flexibility under extreme repetitive mechanical stress while maintaining optical transparency remains challenging because of the intrinsic brittleness of transparent electrodes. Here, we introduce strain-durable ultra-flexible semitransparent OPVs with a thickness below 2 μm. The conformal surface coverage of nanoscale thin metal electrodes (

Pork is known as one of the preferred part of meat worldwide. Especially, the belly, known as ‘Samgyeopsal’in South Korea, has been preferred by consumers in South Korea. Pork belly contained various component muscles, intermuscular and subcutaneous fat. The high-fat belly cut (containing 50%–60% fat ratio) has a low preference in South Korea whereas, the standard belly cut (20%–40% fat ratio) of the consumer preference was different. In addition, the evaluation system focused on lean meat production, represented by loin eye area and back fat thickness. In this review, we discussed the pork belly structure, phenotypic correlation with lean meat production ability and meat quality, and genetic potential to confirm to possibility of application to pig breeding. Moreover, the confirmed possibilities considered that could be a base on the evaluation of standard for the pork belly as an economic trait.

Abstract Recognizing the lesion pattern of antiphospholipid antibody-related stroke (aPL-stroke) may contribute to establishing the cause in patients with cryptogenic stroke. We aimed to describe the neuroimaging features of aPL-stroke compared with atrial fibrillation-related stroke (AF-stroke), a major hidden cause of cryptogenic stroke. Using a prospective stroke registry, we identified consecutive aPL- and AF-stroke patients without other potential causes of stroke. Neuroimaging features based on diffusion-weighted imaging and angiographic findings at admission were compared. A total of 56 and 333 patients were included in the aPL- and AF-stroke groups, respectively. aPL-stroke patients more often presented with single small lesions (aPL-stroke, 30.4% vs. AF-stroke, 7.5%, p

Regulator of G protein signaling 16 (RGS16) is known to be associated with porcine circovirus type 2 (PCV2). PCV2 associated disease (PCVAD) is a serious problem in the swine industry. The representative symptoms of PCVAD are high viral titer proliferation and decreased average daily gain. In this study, we identified single nucleotide polymorphisms (SNPs) in the RGS16 region, including the upstream region. Of the 22 identified SNPs, rs332913874, rs326071195, and rs318298586 were genotyped in 142 Yorkshire pigs. These SNPs were significantly associated with the PCV2 viral load. Moreover, the haplotype combination was also related to the PCV2 viral load. The haplotype and diplotype analysis also had a significant difference with the PCV2 viral load. Taken together, our results suggest that RGS16 SNPs considerably affect the PCV2 viral load.

Closely correlated expression patterns between ubiquitin specific peptidase 9X-linked (USP9X) and adherens junction formation factor (Afadin) in mouse testis development suggests that Usp9x regulates the deubiquitination of Af-6 (also known as Afadin, AFDN), and subsequently, the cell adhesion dynamics during gametogenesis. However, this relationship has not yet been tested in other domestic animals. The study was examined the temporal and spatial expression patterns of porcine USP9X and AFDN from the pre-pubertal to adult stages using real time-PCR and immunohistochemistry. Furthermore, we detected the transcripts of USP9X and AFDN in the testis of 1-, 6- and 12-months old boar, respectively. USP9X and AFDN were found to have similar expressions patterns, with basal expression after 1 month followed by a significant up-regulation from 6 months (puberty) onwards. In addition, neither the AFDN or USP9X proteins were detected in spermatogenic cells but they were expressed in the leydig cells and sertoli cells. USP9X was detected around the basal lamina during pre-puberty, and predominantly expressed in the leydig cells at puberty. Finally, in adult testis, USP9X was increased at the sertoli cell-cell interface and the sertoli cell-spermatid interface. In summary, closely correlated expression patterns between USP9X and AFDN in boar testis supports the previous findings in mice. Furthermore, the junction connections between the sertoli cells may be regulated by the ubiquitination process mediated via USP9X.

Reported herein are solution-processed polymer anode electrodes for blue phosphorescent organic light-emitting diodes (PhOLEDs). The highly conductive anodes were made from 10-wt%-methyl-red-(MR)-doped poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) (PH1000) films. The red-colored and uniform polymer films demonstrated electrical conductivity values that significantly increased from 0.25 to 50 S·cm−1 after doping. The more than 200-fold enhancement in conductivity indicates that the doped films have a lower sheet resistance and better hole injection and transport properties than the pristine films. The resultant PhOLEDs based on the doped polymer anodes exhibited stable, broad, and intense blue emission at 468 nm with a 2616 cd·m−2 maximum luminance and a 4 V turn-on voltage. The obtained study results confirmed the effectiveness of the MR dye as a dopant for the significant enhancement of the conductivity and effective hole injection of PEDOT:PSS. Efficient future flexible optoelectronic applications can be built using this highly conductive polymer electrode obtained via a simple, solution-processed, and cost-effective doping approach.

Abstract Sol–gel indium–gallium–zinc oxide (IGZO) semiconductors are developed as active components of thin‐film transistors (TFTs) because of their high electron mobility, cost‐effective large‐area fabrication, and applicability for flexible substrates. Controlling oxygen vacancies (Vo) in the IGZO semiconductor channel is always problematic for reliable and long‐term operation. Surplus interfacial charges inside the IGZO channel cause negative shifts in threshold voltages (Vth), resulting in depletion‐mode operation and involuntary high current output. The room temperature and rapid (

Regenerative medicine: Understanding regeneration in liver disease A deeper understanding of the biology of liver progenitor cells (LPCs) could give clinicians more effective tools for reversing the effects of liver disease. LPCs are precursors of the liver cells known as hepatocytes, and naturally appear when the tissue is injured or diseased. Juhoon So, Donghun Shin and colleagues at the University of Pittsburgh, USA, have reviewed the current state of knowledge of LPC biology. They explore the mechanisms by which LPCs are generated and activated in response to trauma. These molecular pathways could offer useful drug targets.The authors also point out that excessive LPC activity can promote liver damage and tumorigenesis. As a consequence, any regenerative medicine approach based on LPCs must be coupled with effective strategies for promoting the efficient maturation of these cells into healthy hepatocytes.

ABSTRACTThe MERS-CoV isolated during the 2015 nosocomial outbreak in Korea showed distinctive differences in mortality and transmission patterns compared to the prototype MERS-CoV EMC strain belonging to clade A. We established a BAC-based reverse genetics system for a Korean isolate of MERS-CoV KNIH002 in the clade B phylogenetically far from the EMC strain, and generated a recombinant MERS-CoV expressing red fluorescent protein. The virus rescued from the infectious clone and KNIH002 strain displayed growth attenuation compared to the EMC strain. Consecutive passages of the rescued virus rapidly generated various ORF5 variants, highlighting its genetic instability and calling for caution in the use of repeatedly passaged virus in pathogenesis studies and for evaluation of control measures against MERS-CoV. The infectious clone for the KNIH002 in contemporary epidemic clade B would be useful for better understanding of a functional link between molecular evolution and pathophysiology of MERS-CoV by comparative studies with EMC strain.

This study aims to optimize the proportion and constituents of the mixture used for fabricating 180 MPa ultra-high-strength concrete (UHSC) including coarse aggregate. Various parameters, such as the supplementary cementitious material (SCM) type and amount, water–binder (W/B) ratio, fine and coarse aggregate type and amount, chemical admixture, and mixing process, were considered and their effect on the compressive strength was examined. Based on several experimental tests, the optimized SCM proportions for cement, silica fume (SF), ground-granulated blast furnace slag (BFS), and gypsum are 55%, 20%, 20%, and 5%, respectively. The most appropriate W/B ratio, unit water content, and sand–total aggregate (S/a) ratio are 12.5%, 150 kg/m3, and 0.35, respectively. The use of very fine SF with a specific surface area of 13.7 m2/g and diorite, which is a type of coarse aggregate, improves the compressive strength of UHSC. The optimum amount of superplasticizer ranges between 1.3% and 1.6% and the most suitable slump flow is 750 mm. Finally, for this type of flowable UHSC, a mixing time and speed of 5 min and 40 rpm, respectively, and natural self-compacting without using a tamping bar are recommended. Based on the optimized mix design, UHSC with a compressive strength of 180 MPa can be certainly fabricated. Keywords: Ultra-high-strength concrete, Compressive strength, Supplementary cementitious materials, Self-compaction, Optimum mix design

Coronavirus Disease-2019 (COVID-19) can cause secondary bacterial and fungal infections by affecting the expression of pro-inflammatory markers, such as tumor necrosis alpha and certain cytokines, as well as the numbers of CD4 and CD8 cells. In particular, in the head and neck, various fungal species are naturally present, making it the main route of secondary infection. It is difficult to clearly distinguish whether secondary infection is caused by COVID-19 directly or indirectly as a result of the immunocompromised state induced by drugs used to treat the disease. However, the risk of fungal infection is high in patients with severe COVID-19, and lymphopenia is observed in most patients with the disease. Patients with COVID-19 who are immunosuppressed or have other pre-existing comorbidities are at a significantly higher risk of acquiring invasive fungal infections. In order to reduce morbidity and mortality in these patients, early diagnosis is required, and treatment with systemic antifungal drugs or surgical necrotic tissue resection is essential. Therefore, this review aimed to examine the risk of fungal infection in the head and neck of patients with COVID-19 and provide information that could reduce the risk of mortality.

Quorum sensing signaling molecules are known to be critical determinants in bacterial pathogenesis. Here the authors show the quorum sensing molecule cFP from Vibrio vulnificus inhibits the RIG-I mediated antiviral interferon response and enhances susceptibility to viral infection.

This paper addresses the sampling effect problem in the microgrids consisted of multiple agents; easy example is the distributed generator. We would like to pay attention to the secondary control problem of the microgrids. Inhere, the sampling effect will be analyzed as the main constraint among multiple distributed generators in the microgrids. To do this, the proposed secondary control scheme for the microgrids is modeled by employing a directed graph structure because the microgrids were based on the network communicated through one-way links. By constructing suitable Lyapunov-Krasovskii functional and using some mathematical theory, a sufficient control condition, which is formulated to the consensus protocol form, for the target problem will be derived in terms of LMI. Finally, the simulation example is illustrated to bring the necessity of the analysis of the sampling effect out in operation of the microgrids.

Abstract Successful male germ cell transplantation requires depletion of the host germ cells to allow efficient colonization of the donor spermatogonial stem cells. Although a sterilizing drug, busulfan, is commonly used for the preparation of recipient models before transplantation, the optimal dose of this drug has not yet been defined in dogs. In this study, 1-year-old mongrel dogs were intravenously injected with three different concentrations of busulfan (10, 15, or 17.5 mg/kg). Four weeks after busulfan treatment, no fully matured spermatozoa were detected in any of the busulfan-treated groups. However, small numbers of PGP9.5-positive spermatogonia were detected in all treatment groups, although no synaptonemal complex protein-3-positive spermatocytes were detected. Of note, acrosin-positive spermatids were not detected in the dogs treated with 15 or 17.5 mg/kg busulfan, but were detected in the other group. Eight weeks after busulfan treatment, the dogs treated with 10 mg/kg busulfan fully recovered, but those in the other groups did not. PGP9.5-positive spermatogonia were detected in the 10 mg/kg group, and at a similar level as in the control group, but these cells were rarely detected in the 15 and 17.5 mg/kg groups. These results suggest that a dose of 15–17.5 mg/kg is optimal for ablative treatment with busulfan to prepare the recipient dogs for male germ cell transplantation. At least eight weeks should be allowed for recovery. The results of this study might facilitate the production of recipient dogs for male germ cell transplantation and can also contribute to studies on chemotherapy.

This paper investigates the problem of delay-dependent stability for discrete-time systems with time-varying delays. A novel augmented Lyapunov-Krasovskii functional is proposed in deriving stability criteria in which the feasible region is enhanced. Also, an improved summation inequality is developed and applied to find the lower bound of summation inequalities. Via two numerical examples, improved results will be shown by comparing with maximum delay bounds.

Red ginseng (RG) and black ginseng (BG, CJ EnerG) were prepared from fresh ginseng using one and nine cycles of steaming and drying, respectively. This process reduces the molecular weight (MW) of ginsenoside-active compounds in ginseng by removing sugar moieties from their dammaranes. We compared the pharmacokinetic characteristics of ginsenosides between BG comprising mainly low-MW ginsenosides (Rg3, Rg5, Rk1, and Rh1) and RG that predominantly contains high-MW ginsenosides (Rb1, Rb2, Rc, Rd, Re, and Rg1). The safety profiles and tolerability were also studied using a randomized, double-blind, single-dose, crossover clinical trial. A combination of Rb1, Rg1, and Rg3, well-known representative and functional RG components, exhibited a 1 h faster absorption rate (Tmax) and 58% higher exposure (24 h area under the concentration–time curve, AUC24) in BG than in RG. Furthermore, the combination of Rg3, Rg5, and Rk1, the major and most efficient components in BG, displayed 824% higher absorption (AUC24) in BG than in RG. The total ginsenoside showed a 5 h rapid intestinal absorption (Tmax) and 79% greater systemic exposure (AUC24) in BG than in RG. No clinically significant findings were observed in terms of safety or tolerability. Thus, BG extract was more effective than RG extract.

Histone variants act as transcriptional activators and repressors and have been linked to cancer progression. Park and Choi et al. show that the histone H3.3 overexpression is associated with early-stage lung cancer, and promotes cancer cell migration by upregulating a G-protein-coupled receptor.

Objectives. Allergic and nonallergic rhinitis are very common disease for children, however, little is known about their natural courses in the general population. The purpose is to evaluate the natural course of allergic and nonallergic rhinitis in children. Methods. We analyzed data from Snoring Child Cohort of 178 children (107 boys and 71 girls). All children entered the study at the age of 7 years (range, 6.5 to 7.4 years). Questionnaires regarding chronic rhinitis, a skin prick test (SPT) for 5 inhalent allergens, and specific IgE for 2 dust mites were administered. Children were classified into 4 groups: allergic rhinitis (rhinitis, positive SPT), nonallergic rhinitis (rhinitis, negative SPT), sensitization only (no rhinitis, positive SPT), and control (no rhinitis, negative SPT). We repeated follow them annually, and analyzed the data of first and third year for this study. Results. Finally, the data of 122 children were analyzed. Among 18 children with allergic rhinitis at 7 years, 13 (72%) became sensitization only after 2 years and 5 (28%) were remained having allergic rhinitis. Five out of 19 children (26%) with nonallergic rhinitis developed into allergic rhinitis and 7 (37%) into control at 9 years. Twenty-four out of 28 children (86%) with sensitization only at 7 years remained the same at 9 years. Among 57 control children at 7 years, 2 (4%) developed into allergic rhinitis, 7 (12%) with nonallergic rhinitis, and 16 (28%) with sensitization only at 9 years. Conclusion. The status of chronic rhinitis and allergen sensitization is ever-changing in children.

ObjectivesTo evaluate the association between catecholamine levels and skin prick test results among children.MethodsTwo hundred eight first grade children from one elementary school were invited to participate in this study. Skin prick test (SPT) for six allergens (2 house dust mites, cat, dog, mugwort, and pollen mixture) was performed, and patient demographic information was recorded. The parents were surveyed using questionnaires about rhinitis-related symptoms. Finally, venous blood sampling was done to measure catecholamine levels (epinephrine, norepinephrine, and dopamine) by high-performance liquid chromatography.ResultsOut of 208 children, 174 (106 boys and 68 girls) enrolled in this study. Ninety-six of the children (55%) had negative SPT (nonsensitization group), while 78 (45%) had a positive SPT to at least one of six allergens (sensitization group). The diagnosis of chronic rhinitis was more prevalent in the sensitization group (35.9%) than nonsensitization group (26.0%), however the finding was not significant (P=0.186). Epinephrine levels were decreased between the sensitization group compared to the nonsensitization group (P=0.004). There was no difference in norepinephrine and dopamine levels (P>0.05).ConclusionEpinephrine levels are lower in children with positive SPT compared to controls, however, the level of the catecholamine was not associated with the presence or absence of rhinitis symptoms.

Cerebral small vessel disease (SVD), which includes white matter hyperintensities (WMHs), silent brain infarction (SBI), and cerebral microbleeds (CMBs), develops in a conjunction of cumulated injuries to cerebral microvascular beds, increased permeability of blood-brain barriers, and chronic oligemia. SVD is easily detected by routine neuroimaging modalities such as brain computed tomography or magnetic resonance imaging. Research has revealed that the presence of SVD markers may increase the risk of future vascular events as well as deteriorate functional recovery and neurocognitive trajectories after stroke, and such an association could also be applied to hemorrhagic stroke survivors. Currently, the specific mechanistic processes leading to the development and manifestation of SVD risk factors are unknown, and further studies with novel methodological tools are warranted. In this review, recent studies regarding the prognostic impact of WMHs, SBI, and CMBs on stroke survivors and briefly summarize the pathophysiological concepts underlying the manifestation of cerebral SVD.

Three strains of the green microalga Botryococcus braunii (JJS, KCM, and KJD) were isolated from different water bodies in Korea and grown as batch cultures in the laboratory. The effects of different growth media and temperatures on the growth rate were investigated, as well as the effect of temperature on the total lipid content and lipid profile. All three strains had the highest growth rates in BG-11 medium and at 25°C. Maximal lipid production (g L-1) was at 30°C in the JJS strain and at 25°C in the KCM and KJD strains. However, all the three strains produced the greatest percent dry weight of total lipids at 15°C and had the lowest percent dry weight of total lipids at 25°C. In general, oleic acid, linolenic acid, and behenic acid were the most common fatty acids in all three strains. However, the three strains varied considerably in their fatty acid profiles at different culture temperatures.

BackgroundThe current guideline recommends moderate‐ to vigorous‐intensity physical activity (PA) at least 40 min/day for 3 to 4 days/week. Although recent evidence has demonstrated that low‐dose PA could reduce cardiovascular mortality, the relationship between low‐dose PA and the risk of stroke remains uncertain. Methods and ResultsUsing data from a nation‐wide sample cohort in Korea, we examined 336 326 individuals who received a general health examination between 2009 and 2010. Level of PA was assessed using a questionnaire for weekly PA frequencies regarding 3 intensity categories: light, moderate, and vigorous. Moderate‐ to vigorous‐intensity PA (MVPA) was classified into 4 frequency categories: none, 1 to 2, 3 to 4, or ≥5 times/week. Cox proportional hazard models were constructed to estimate the risk of stroke. During the average follow‐up of 3.6 years, 2213 stroke cases occurred. MVPA was none in 50%, 1 to 2 times/week in 20%, 3 to 4 times/week in 13%, and ≥5 times/week in 18% of the cohort. Individuals with MVPA 1 to 2 times/week had a 16% reduced risk of stroke (adjusted hazard ratio, 0.84; 95% confidence interval, 0.73–0.96) compared with those with no MVPA. The population attributable fraction of no MVPA was 12%, which was the second most important risk factor for a stroke after hypertension. ConclusionsEven 1 to 2 times a week of MVPA might be beneficial to prevent a first‐ever stroke in the general population, although a quantitative validation of the questionnaire is needed. From a public health perspective, we need to encourage inactive people to start exercising with more‐achievable goals.

Glycemic variability (GV) is reportedly a predictor for poor outcome in various clinical conditions. We aimed to assess whether GV during hospital admission is associated with poor outcomes in patients with acute ischemic stroke (AIS) and diabetes. We prospectively enrolled consecutive patients with AIS from the registry of 6 tertiary hospitals between January 2013 and December 2014. For the GV index, we used a glucose level range that was divided into 4 quartiles. Multivariable binary and ordinal logistic regression analyses were performed to determine the association between GV and the modified Rankin Scale score (3-6) at 3 months. We enrolled 1,504 patients with AIS and diabetes (mean age, 68.1 years; male, 57.2%), of which 35.1% had poor outcomes at 3 months. An increasing glucose range quartile was positively associated with initial neurologic severity and development of hypoglycemia during hospital admission. Multivariable analysis showed that the glucose level range quartile was associated with poor outcomes, even after adjusting for the number of glucose measurement and hypoglycemia (odds ratio [OR] Q2 vs. Q1: 1.50, 95% confidence interval [CI]: 1.02-2.18; OR Q3 vs. Q1: 2.01, 95% CI: 1.34-3.01; OR Q4 vs. Q1: 1.98, 95% CI: 1.22-3.23). These associations remained significant after dichotomization according to glycated hemoglobin levels at admission. An increasing glucose level range as a GV index during hospital admission was associated with poor functional outcomes at 3 months in patients with AIS and diabetes.

ObjectivesObstructive sleep apnea (OSA) is a disorder characterized by repetitive partial or complete occlusion of the upper airway during sleep that affects quality of life. The aim of this study was to develop the Korean version of the sleep apnea quality of life index (K-SAQLI) and apply it in Korean patients with OSA.MethodsNinety-three patients with OSA completed the K-SAQLI. Its construct validity and responsiveness were tested by comparing the baseline and change scores obtained in each domain (i.e., daily functioning, social interactions, emotional functioning, and symptoms) using the medical outcome survey-short form 36 (SF-36).ResultsThe Cronbach α coefficients of internal reliability exceeded 0.60 in all the domains (daily functioning, 0.89; social interactions, 0.88; emotional functioning, 0.92; symptoms, 0.67; and total, 0.94). The K-SAQLI had a high test-retest correlation coefficient of 0.73 in the 20 randomized selected patients. The construct validity was confirmed by significant correlations with SF-36 subscale scores.ConclusionThe results of this study demonstrate that the K-SAQLI may be applicable for clinical purposes.

Background and Objectives: Previous studies found differences in the characteristics of NOTCH3 mutations in Caucasians and Asians with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Therefore, we sought to investigate the correlations between genetic and clinical/radiological findings in Korean CADASIL patients including some variants of unknown significance (VUS). Materials and Methods: We screened 198 patients with a suspected diagnosis of CADASIL between 2005 and 2015 via Sanger sequencing. Results: A total of 34 subjects (52.5 ± 9.5 years) were included. The majority of the mutations were in exon 3 and exon 11. R75P mutations (n = 5), followed by Y465C and R544C mutations (n = 4) were the most prevalent. Patients with those mutations exhibited less frequent anterior temporal (AT) or external capsular (EC) hyperintensities compared to patients with other locus mutations. Hemorrhagic stroke (HS) was found to be associated with mutations in exon 3 (R75P), exon 9 (Y465C), exon 11 (R587C), and exon 22 (R1175W variants), which were common locations in our study. Although it is unclear that genetic differences might affect the phenotypes in ethnicities, Asian population shows less migraine or seizure, but more intracerebral hemorrhage. Unlike in westernized countries, typical AT or EC hyperintensities may not be significant MRI markers, at least in Korean CADASIL patients. Furthermore, similar to R75P phenotypes, it is a novel finding that patients with Y465C and R1175W VUS have less frequent AT involvement than Caucasians. Conclusion: The associations between HS and common genetic locations account for the increased development of intracerebral hemorrhage in Koreans rather than Caucasians. We suggest that some CADASIL mutations appear to impart novel region-specific characteristics.

Cerebral microbleeds (CMBs) are tiny, round dark-signal lesions that are most often detected on gradient-echo MR images. CMBs consist of extravasations of blood components through fragile microvascular walls characterized by lipohyalinosis and surrounding macrophages. The prevalence of CMBs in elderly subjects with no history of cerebrovascular disease is around 5%, but is much higher in patients with ischemic or hemorrhagic stroke. Development of CMBs is closely related to various vascular risk factors; in particular, lobar CMBs are thought to be associated with cerebral amyloid angiopathy. The presence of CMBs has been hypothesized to reflect cerebral-hemorrhage-prone status in patients with hypertension or amyloid microangiopathy. Stroke survivors with CMBs have been consistently found to have an elevated risk of subsequent hemorrhagic stroke or an antithrombotic-related hemorrhagic complication, although studies have failed to establish a link between CMBs and hemorrhagic transformation after thrombolytic treatment. A large prospective study is required to clarify the clinical significance of CMBs and their utility in a decision-making index.

The liver-specific microRNA miR-122, which has essential roles in liver development and metabolism, is a key proviral factor for hepatitis C virus (HCV). Despite its crucial role in the liver and HCV life cycle, little is known about the molecular mechanism of miR-122 expression regulation by HCV infection. Here, we show that the HCV core protein downregulates the abundance of miR-122 by promoting its destabilization via the inhibition of GLD-2, a non-canonical cytoplasmic poly(A) polymerase. The decrease in miR-122 expression resulted in the dysregulation of the known functions of miR-122, including its proviral activity for HCV. By high-throughput sequencing of small RNAs from human liver biopsies, we found that the 22-nucleotide (nt) prototype miR-122 is modified at its 3' end by 3'-terminal non-templated and templated nucleotide additions. Remarkably, the proportion of miR-122 isomers bearing a single nucleotide tail of any ribonucleotide decreased in liver specimens from patients with HCV. We found that these single-nucleotide-tailed miR-122 isomers display increased miRNA activity and stability over the 22-nt prototype miR-122 and that the 3'-terminal extension is catalyzed by the unique terminal nucleotidyl transferase activity of GLD-2, which is capable of adding any single ribonucleotide without preference of adenylate to the miR-122 3' end. The HCV core protein specifically inhibited GLD-2, and its interaction with GLD-2 in the cytoplasm was found to be responsible for miR-122 downregulation. Collectively, our results provide new insights into the regulatory role of the HCV core protein in controlling viral RNA abundance and miR-122 functions through miR-122 stability modulation.

[This corrects the article DOI: 10.1371/journal.pbio.1002152.].

The hepatitis C virus (HCV) internal ribosome entry site (IRES) that directs cap-independent viral translation is a primary target for small interfering RNA (siRNA)-based HCV antiviral therapy. However, identification of potent siRNAs against HCV IRES by bioinformatics-based siRNA design is a challenging task given the complexity of HCV IRES secondary and tertiary structures and association with multiple proteins, which can also dynamically change the structure of this cis-acting RNA element. In this work, we utilized siRNA tiling approach whereby siRNAs were tiled with overlapping sequences that were shifted by one or two nucleotides over the HCV IRES stem-loop structures III and IV spanning nucleotides (nts) 277-343. Based on their antiviral activity, we mapped a druggable region (nts 313-343) where the targets of potent siRNAs were enriched. siIE22, which showed the greatest anti-HCV potency, targeted a highly conserved sequence across diverse HCV genotypes, locating within the IRES subdomain IIIf involved in pseudoknot formation. Stepwise target shifting toward the 5' or 3' direction by 1 or 2 nucleotides reduced the antiviral potency of siIE22, demonstrating the importance of siRNA accessibility to this highly structured and sequence-conserved region of HCV IRES for RNA interference. Nanoparticle-mediated systemic delivery of the stability-improved siIE22 derivative gs_PS1 siIE22, which contains a single phosphorothioate linkage on the guide strand, reduced the serum HCV genome titer by more than 4 log10 in a xenograft mouse model for HCV replication without generation of resistant variants. Our results provide a strategy for identifying potent siRNA species against a highly structured RNA target and offer a potential pan-HCV genotypic siRNA therapy that might be beneficial for patients resistant to current treatment regimens.

Background: Lacunar infarctions account for up to 25% of all ischemic strokes and, thus, constitute a numerically important subgroup. It is important that the two pathogeneses of lacunar infarction, that is, small-vessel occlusion and branch atheromatous disease, be differentiated because prognoses and treatment strategies differ. The authors evaluated the presence of branch atheromatous plaque in parent arteries that supply lacunar infarcts by high-resolution magnetic resonance imaging (HR-MRI). Methods: HR-MRI was performed in 15 patients with (1) a clinical presentation consistent with classical lacunar syndromes; (2) an acute lacunar infarction by diffusion-weighted imaging, measuring ≤20 mm in maximal diameter; (3) a magnetic resonance angiography showing a normal middle cerebral artery or basilar artery supplying the ischemic lesion, and (4) no other obvious etiology for small-vessel distribution ischemic stroke. Results: The median time of vessel wall imaging after index events was 4 days (range, 2–15 days). Six of the 15 patients had a lacunar infarction in the middle cerebral artery territory, and 9 had a lesion in the basilar artery territory. HR-MRI detected underlying atheromatous plaques in 9 patients (60%) with a lacunar infarction. In these 9 patients, asymptomatic intracranial atherosclerotic stenosis was more frequent compared to patients without branch atheromatous plaque (55.6 vs. 16.7%). In pontine infarctions, ischemic lesions that extended to the pial base of the pons were more frequent in patients with branch atheromatous plaques (83.3 vs. 33.3%), and all the ischemic lesions and atheromatous plaques were on the same side (right, n = 2; left, n = 4). All plaques responsible for acute symptomatic lacunar infarction were enhanced in contrast-enhanced T1-weighted HR-MR images. Conclusions: HR-MRI results enabled underlying symptomatic branch atheromatous disease to be detected in lacunar infarction patients. The experience gained during this study indicates that HR-MRI better delineates intracranial arterial lesions, suggesting that its use will lead to a further understanding of the mechanisms involved in stroke.

Epidermal growth factor receptor variant III (EGFRvIII) has been associated with glioma stemness, but the direct molecular mechanism linking the two is largely unknown. Here, we show that EGFRvIII induces the expression and secretion of pigment epithelium-derived factor (PEDF) via activation of signal transducer and activator of transcription 3 (STAT3), thereby promoting self-renewal and tumor progression of glioma stem cells (GSCs). Mechanistically, PEDF sustained GSC self-renewal by Notch1 cleavage, and the generated intracellular domain of Notch1 (NICD) induced the expression of Sox2 through interaction with its promoter region. Furthermore, a subpopulation with high levels of PEDF was capable of infiltration along corpus callosum. Inhibition of PEDF diminished GSC self-renewal and increased survival of orthotopic tumor-bearing mice. Together, these data indicate the novel role of PEDF as a key regulator of GSC and suggest clinical implications.

Unlike experimental studies indicating a neuroprotective property of uric acid, clinical studies have shown that elevated levels of uric acid are associated with a risk of ischemic stroke. However, the association of uric acid with cerebral hemorrhage has seldom been tested. We aimed to elucidate the association between uric acid and cerebral microbleeds (CMBs), a hemorrhage-prone cerebral microangiopathy. Seven hundred twenty-four patients with ischemic stroke who were consecutively admitted to our hospital were included in this study. We collected demographic, clinical, and laboratory data, including uric acid level, and examined the presence of CMBs using T2*-weighted gradient-echo MRI. We used logistic regression analysis to examine an independent association between uric acid and CMBs. Two-hundred twenty-six patients had CMBs (31.2%). After adjusting for possible confounders, elevated uric acid was independently associated with the presence of CMBs (the highest quartile vs. lowest quartile, adjusted odd ratio [OR], 1.98; 95% confidence interval [CI], 1.16-3.39). This association retained in patients with deep or infratentorial CMBs (with or without lobar CMBs) but not among those with lobar CMBs. In addition, this association was robust among patients with hypertension (the highest quartile vs. lowest quartile, adjusted OR, 2.74; 95% CI, 1.43-5.24). In contrast, we did not find the association in patients without hypertension. We demonstrated that serum uric acid is independently associated with the presence of CMBs. In particular, the relation between uric acid and CMBs was robust in hypertensive patients.

An active debate has been underway on the magnitude and duration of carbon (C) emissions from hydroelectric reservoirs, yet little attention has been paid to stochastic C emissions from reservoir sediments during extreme climatic events. A rare opportunity for field measurements of CO _2 efflux from a hydroelectric reservoir in Korea during an extreme drought event was used to examine how prolonged droughts can affect microbial organic matter processing and the release of CO _2 , CH _4 and N _2 O from exposed sediments. Chamber measurements of CO _2 efflux along an exposed sediment transect, combined with high-frequency continuous sensor measurements of the partial pressure of CO _2 (pCO _2 ) in the reservoir surface water, exhibited extraordinary pulses of CO _2 from exposed sediments and the turbulent inflowing water in contrast to a small CO _2 sink in the main water body of the reservoir and a low efflux of CO _2 from the flooded sediment. Significant increases in the production of CO _2 , CH _4 and N _2 O observed in a laboratory incubation of sediments, together with enhanced activities of phenol oxidase and three hydrolases, indicate a temporary activation of microbial organic matter processing in the drying sediment. The results suggest that drought-triggered pulses of greenhouse gas emission from exposed sediments can offset the C accumulation in reservoir sediments over time scales of years to decades, reversing the trend of declining C emissions from aging reservoirs.

The p53 tumor suppressor function can be compromised in many tumors by the cellular antagonist HDM2 and human papillomavirus oncogene E6 that induce p53 degradation. Restoration of p53 activity has strong therapeutic potential. Here, we identified TSC-22 as a novel p53-interacting protein and show its novel function as a positive regulator of p53. We found that TSC-22 level was significantly down-regulated in cervical cancer tissues. Moreover, over-expression of TSC-22 was sufficient to inhibit cell proliferation, promote cellular apoptosis in cervical cancer cells and suppress growth of xenograft tumors in mice. Expression of also TSC-22 enhanced the protein level of p53 by protecting it from poly-ubiquitination. When bound to the motif between amino acids 100 and 200 of p53, TSC-22 inhibited the HDM2- and E6-mediated p53 poly-ubiquitination and degradation. Consequently, ectopic over-expression of TSC-22 activated the function of p53, followed by increased expression of p21(Waf1/Cip1) and PUMA in human cervical cancer cell lines. Interestingly, TSC-22 did not affect the interaction between p53 and HDM2. Knock-down of TSC-22 by small interfering RNA clearly enhanced the poly-ubiquitination of p53, leading to the degradation of p53. These results suggest that TSC-22 acts as a tumor suppressor by safeguarding p53 from poly-ubiquitination mediated-degradation.

Aberrant miR-21 expression is closely associated with cell proliferation, anti-apoptosis, migration, invasion, and metastasis in various cancers. However, the regulatory mechanism of miR-21 biogenesis is largely unknown. Here, we demonstrated that the tumor suppressor PTEN negatively regulates the expression of oncogenic miR-21 at the post-transcriptional level. Moreover, our results suggest that PTEN plays such a role through the indirect interaction with the Drosha complex. To elucidate how PTEN regulates pri- to pre-miR-21 processing, we attempted to find PTEN-interacting proteins and identified an RNA-regulatory protein, RNH1. Using the sensor to monitor pri-miR-21 processing, we demonstrated that RNH1 is necessary and sufficient for pri-miR-21 processing. Moreover, our results propose that the nuclear localization of RNH1 is important for this function. Further analysis showed that RNH1 directly interacts with the Drosha complex and that PTEN blocks this interaction. Taken together, these results suggest that the PTEN-mediated miR-21 regulation is achieved by inhibiting the interaction between the Drosha complex and RNH1, revealing previously unidentified role of PTEN in the oncogenic miR-21 biogenesis.