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PurposeThe aim of this study was to determine whether school-aged children with Kawasaki disease (KD) have an increased risk for early atherosclerosis.MethodsThe study included 98 children. The children were divided into the following groups: group A (n=19), KD with coronary arterial lesions that persisted or regressed; group B (n=49), KD without coronary arterial lesions; and group C (n=30), healthy children. Anthropometric variables and the levels of biochemical markers, including total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A, apolipoprotein B, homocysteine, high-sensitivity C-reactive protein (hs-CRP), and brachial artery stiffness using pulse wave velocity were compared among the three groups.ResultsThere were no significant differences in blood pressure and body index among the three groups. Additionally, there was no sex-specific difference. Moreover, the levels of triglyceride, HDL-C, apolipoprotein A, and hs-CRP did not differ among the three groups. However, the levels of total cholesterol (P=0.018), LDL-C (P=0.0003), and apolipoprotein B (P=0.029) were significantly higher in group A than in group C. Further, the level of homocysteine and the aortic pulse wave velocity were significantly higher in groups A and B than in group C (P=0.0001).ConclusionSchool-aged children after KD have high lipid profiles and arterial stiffness indicating an increased risk for early atherosclerosis.

Abstract Background Livestock-associated Staphylococcus aureus (LA-SA) has gained global attention because of its ability to colonize farm animals and transmit to the environment and humans, leading to symptomatic infections and the spread of antimicrobial resistance (AMR). In the last decade, numerous studies have reported a high prevalence of S. aureus clonal complex (CC) 398 in pig farms. Results In this study, 163 S. aureus isolates were collected from healthy pigs (n = 110), farm environments (n = 42), and farm workers (n = 11), and their AMR profiles and epidemiological characteristics were analyzed. We identified 51 (31.3%) methicillin-resistant S. aureus (MRSA) and 112 (68.7%) methicillin-susceptible S. aureus (MSSA), with 161 (98.8%) isolates belonging to the CC398 lineage. The highest prevalence of spa type t571 was observed among the CC398 isolates. All 47 sequence type (ST) 398 MRSA isolates carried staphylococcal cassette chromosome mec (SCCmec) V, while four ST541 isolates carried SCCmec IV. High levels of resistance to commonly used antibiotics, including phenicols, quinolones, lincosamides, macrolides, aminoglycosides, and tetracyclines, have been observed on Korean pig farms. Notably, 21 cfr-positive CC398 isolates (four ST541-SCCmec IV MRSA and 17 ST398 MSSA) displaying increased resistance to linezolid were identified in healthy pigs. Conclusions In summary, these findings suggest that the multidrug-resistant CC398 S. aureus lineage predominantly colonizes healthy pigs and farm environments in Korea. The emergence of cfr-positive S. aureus at human-animal interfaces presents a significant threat to food safety and public health.

PurposeSerum alkaline phosphatase (ALP) level is the most valid marker of bone formation. Precocious puberty (PP) in girls is characterized by early growth acceleration. The aim of this study was to determine whether serum ALP levels differ between girls with PP and those with normal puberty, and whether ALP level varies with age or Tanner stage.MethodsThis retrospective study included girls with PP (n=61) and normal puberty (n=71) who visited the outpatient clinic at Department of Pediatrics, Chungnam National University Hospital from March 2010 to August 2011. We obtained age, height, parental height, weight, bone age, Tanner stage, and concentrations of luteinizing hormone, follicular-stimulating hormone, estradiol, ALP, and insulin-like growth factor-1 (IGF-1) from the participants' medical records.ResultsAge and predicted adult height were significantly lower in girls with PP than in those with normal puberty. The height standard deviation score (SDS), weight SDS, body mass index, midparental height, bone age, and IGF-1 level were higher in girls with PP than in those with normal puberty. ALP level was significantly higher in 5- to 8-year-old girls with PP than in age-matched girls with normal puberty. The mean ALP levels were higher in girls with PP than bone age-matched girls with normal puberty (P=0.0003)ConclusionSerum ALP level showed the significance differences between girls with PP and those with normal puberty. The reasons for and the mechanisms underlying this elevation in serum ALP level in girls with PP should be investigated further.

Lactic acid bacteria (LAB) are probiotic microorganisms widely used for their health benefits in the food industry. However, recent concerns regarding their safety have highlighted the need for comprehensive safety assessments. In this study, we aimed to evaluate the safety of L. bulgaricus IDCC 3601, isolated from homemade plain yogurt, via genomic, phenotypic, and toxicity-based analyses. L. bulgaricus IDCC 3601 possessed a single circular chromosome of 1,865,001 bp, with a GC content of 49.72%, and 1910 predicted coding sequences. No virulence or antibiotic resistance genes were detected. Although L. bulgaricus IDCC 3601 exhibited antibiotic resistance to gentamicin and kanamycin, this resistance is an intrinsic feature of this species. L. bulgaricus IDCC 3601 did not produce biogenic amines and did not exhibit hemolytic activity. Phenotypic analysis of enzyme activity and carbohydrate fermentation profiles revealed the metabolic features of L. bulgaricus IDCC 3601. Moreover, no deaths or abnormalities were observed in single-dose oral toxicity tests, suggesting that L. bulgaricus IDCC 3601 has no adverse effect on human health. Finally, L. bulgaricus IDCC 3601 inhibited the growth of potential carbapenem-resistant Enterobacteriaceae. Therefore, our results suggest that L. bulgaricus IDCC 3601 is a safe probiotic strain for human consumption.

Background/Aims Despite the availability of direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection in Korea, need remains for pangenotypic regimens that can be used in the presence of hepatic impairment, comorbidities, or prior treatment failure. We investigated the efficacy and safety of sofosbuvir–velpatasvir and sofosbuvir–velpatasvir–voxilaprevir for 12 weeks in HCV-infected Korean adults. Methods This Phase 3b, multicenter, open-label study included 2 cohorts. In Cohort 1, participants with HCV genotype 1 or 2 and who were treatment-naive or treatment-experienced with interferon-based treatments, received sofosbuvir–velpatasvir 400/100 mg/day. In Cohort 2, HCV genotype 1 infected individuals who previously received an NS5A inhibitor-containing regimen ≥ 4 weeks received sofosbuvir–velpatasvir–voxilaprevir 400/100/100 mg/day. Decompensated cirrhosis was an exclusion criterion. The primary endpoint was SVR12, defined as HCV RNA < 15 IU/mL 12 weeks following treatment. Results Of 53 participants receiving sofosbuvir–velpatasvir, 52 (98.1%) achieved SVR12. The single participant who did not achieve SVR12 experienced an asymptomatic Grade 3 ASL/ALT elevation on day 15 and discontinued treatment. The event resolved without intervention. All 33 participants (100%) treated with sofosbuvir–velpatasvir–voxilaprevir achieved SVR 12. Overall, sofosbuvir–velpatasvir and sofosbuvir–velpatasvir–voxilaprevir were safe and well tolerated. Three participants (5.6%) in Cohort 1 and 1 participant (3.0%) in Cohort 2 had serious adverse events, but none were considered treatment-related. No deaths or grade 4 laboratory abnormalities were reported. Conclusions Treatment with sofosbuvir–velpatasvir or sofosbuvir–velpatasvir–voxilaprevir was safe and resulted in high SVR12 rates in Korean HCV patients.

Synchronization is a key topic of research in neuroscience, medicine, and artificial neural networks; however, understanding its principle is difficult, both scientifically and mathematically. Specifically, the synchronization of the FitzHugh-Nagumo network with a hierarchical architecture has previously been studied; however, a mathematical analysis has not been conducted, owing to the network complexity. Therefore, in this paper, we saught to understand synchronization through mathematical analyses. In particular, we consider the most common types of hierarchical architecture and present a condition of the hierarchical architecture to induce synchronization. First, we provide mathematical analyses of a Lyapunov function for each layer, from which we obtain sufficient conditions guaranteeing synchronization and show that the Lyapunov function decreases exponentially. Moreover, we show that the internal connectivity critically affects synchronization in the first layer; however, in the second and subsequent layers, the internal connectivity is not important for synchronization, and the connectivity up to the first layer critically affects synchronization. We expect that the results and mathematical methodology can be applied to study other similar neural models with hierarchical architectures.

Diabetes is often associated with reduced muscle mass and function. The ketogenic diet (KD) may improve muscle mass and function via the induction of nutritional ketosis. To test whether the KD is able to preserve muscle mass and strength in a mouse model of type 2 diabetes (T2DM), C57BL/6J mice were assigned to lean control, diabetes control, and KD groups. The mice were fed a standard diet (10% kcal from fat) or a high-fat diet (HFD) (60% kcal from fat). The diabetic condition was induced by a single injection of streptozotocin (STZ; 100 mg/kg) and nicotinamide (NAM; 120 mg/kg) into HFD-fed mice. After 8-week HFD feeding, the KD (90% kcal from fat) was fed to the KD group for the following 6 weeks. After the 14-week experimental period, an oral glucose tolerance test and grip strength test were conducted. Type 2 diabetic condition induced by HFD feeding and STZ/NAM injection resulted in reduced muscle mass and grip strength, and smaller muscle fiber areas. The KD nutritional intervention improved these effects. Additionally, the KD altered the gene expression of nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome- and endoplasmic reticulum (ER) stress-related markers in the muscles of diabetic mice. Collectively, KD improved muscle mass and function with alterations in NLRP3 inflammasome and ER stress.

Abstract Stress management is necessary for vertebrate survival. Chronic stress drives depression by excitation of the lateral habenula (LHb), which silences dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neuronal projection from the rostromedial tegmental nucleus (RMTg). However, the effect of acute stress on this LHb-RMTg-VTA pathway is not clearly understood. Here, we used fluorescent in situ hybridisation and in vivo electrophysiology in mice to show that LHb aromatic l-amino acid decarboxylase-expressing neurons (D-neurons) are activated by acute stressors and suppress RMTg GABAergic neurons via trace aminergic signalling, thus activating VTA dopaminergic neurons. We show that the LHb regulates RMTg GABAergic neurons biphasically under acute stress. This study, carried out on male mice, has elucidated a molecular mechanism in the efferent LHb-RMTg-VTA pathway whereby trace aminergic signalling enables the brain to manage acute stress by preventing the hypoactivity of VTA dopaminergic neurons.

Abstract Bioluminescence imaging is useful for non-invasively monitoring inflammatory reactions associated with disease progression, and since NF-κB is a pivotal transcription factor that alters expressions of inflammatory genes, we generated novel NF-κB luciferase reporter (NF-κB-Luc) mice to understand the dynamics of inflammatory responses in whole body, and also in various type of cells by crossing NF-κB-Luc mice with cell-type specific Cre expressing mice (NF-κB-Luc:[Cre]). Bioluminescence intensity was significantly increased in NF-κB-Luc (NKL) mice exposed to inflammatory stimuli (PMA or LPS). Crossing NF-κB-Luc mice with Alb-cre mice or Lyz-cre mice generated NF-κB-Luc:Alb (NKLA) and NF-κB-Luc:Lyz2 (NKLL) mice, respectively. NKLA and NKLL mice showed enhanced bioluminescence in liver and macrophages, respectively. To confirm that our reporter mice could be utilized for the non-invasive monitoring of inflammation in preclinical models, we conducted a DSS-induced colitis model and a CDAHFD-induced NASH model in our reporter mice. In both models, our reporter mice reflected the development of these diseases over time. In conclusion, we believe that our novel reporter mouse can be utilized as a non-invasive monitoring platform for inflammatory diseases.

Mutations in BRCA1/2 are associated with a homologous recombination deficiency phenotype in BRCA-associated cancers. Reversion mutations can restore BRCA1/2 function and result in treatment resistance in these cancer-types. Here, the authors show that, in select cases, reversion mutations in BRCA1/2 can indicate prior BRCA-mediated tumorigenesis in non-canonical histologies.

Abstract The terpolymer (PFS–GMA–TFEMA) was prepared and coated on silica waveguide for polymeric optical overclad. In our study, athermal characteristics were realised by adjusting the coefficient of negative thermal expansion of the synthesised terpolymer overclad, and the positive thermo‐optic coefficient of the silica thin film. The measured values were −1.11 × 10–4 /K and 0.79 × 10–5 /K (dn/dT). The thermal properties according to the temperature change indicated that the wavelength had shifted by about 0.15 nm from 20 to 90°C, with little change over 50°C. When the temperature increased, the wavelength shift of the silica/terpolymer hybrid arrayed waveguide grating was −0.002 nm/°C, compared to the 0.01 nm/°C of silica arrayed waveguide grating. Terpolymer overclad arrayed waveguide grating showed a centre wavelength loss of 5.334 dB, loss uniformity of 0.864 dB, a polarisation dependent loss of 0.162 dB, and a non‐adjacent crosstalk of −31.67 dB.

The recent announcement by the European Union of the Fit for 55 Package and a prospective ban on the sale of new internal combustion engine vehicles by 2035 has prompted a notable surge in the electric vehicle (EV) market. The shift toward EVs concurrently presents challenges, namely the resource management of used EV batteries, particularly their reuse, recycling, and remanufacturing. Accordingly, this study aims to analyze the effects of the reduced environmental impacts of a remanufactured portable power station (RPPS) compared with those of a new portable power station (NPPS) using life cycle assessment (LCA) and the economic benefits gained from reusing used EV batteries. The results of the LCA of the RPPS indicated a notable environmental advantage, with reductions of 42.01% in GWP and 41.91% in ADP compared with those achieved by the NPPS. Moreover, the economic benefits of the waste battery remanufacturing business amounted to USD 593,212 at an annual sales volume of 1000 units. The environmental benefits of remanufacturing practices represent valuable support for policies centered on remanufacturing and reusing used EV batteries. The findings of this study could stimulate a future market for products repurposed from used EV batteries, thereby further fostering sustainability in this sector.

Abstract The habenula (Hb) is an epithalamic structure that links multiple forebrain areas with the mid/hindbrain monoaminergic systems. As an anti-reward center, it has been implicated in the etiology of various neuropsychiatric disorders, particularly those associated with dysregulated reward circuitry. In this regard, Hb has been proposed as a therapeutic target for treatment-resistant depression associated with a higher risk of suicide. Therefore, we aimed to gain insight into the molecular signatures of the Hb in association with suicide in individuals with major depression. Postmortem gene expression analysis identified 251 differentially expressed genes (DEGs) in the Hb tissue of suicides in comparison with Hb tissues from neurotypical individuals. Subsequent bioinformatic analyses using single-cell transcriptome data from the mouse Hb showed that the levels of a subset of endothelial cell-enriched genes encoding cell–cell junctional complex and plasma membrane-associated proteins, as well as the levels of their putative upstream transcriptional regulators, were significantly affected in suicides. Although our findings are based on a limited number of samples, the present study suggests a potential association of endothelial dysfunction in the Hb with depression and suicidal behavior.

Sequence type (ST) 5 methicillin-resistant Staphylococcus aureus (MRSA) with staphylococcal cassette chromosome mec (SCCmec) type II (ST5-MRSA-II) and ST72-MRSA-IV represent the most significant genotypes for healthcare- (HA) and community-associated (CA) MRSA in Korea, respectively. In addition to the human-type MRSA strains, the prevalence of livestock-associated (LA) MRSA clonal lineages, such as ST541 and ST398 LA-MRSA-V in pigs and ST692 LA-MRSA-V and ST188 LA-MRSA-IV in chickens, has recently been found. In this study, clonotype-specific resistance profiles to cathelicidins derived from humans (LL-37), pigs (PMAP-36), and chickens (CATH-2) were examined using six different ST groups of MRSA strains: ST5 HA-MRSA-II, ST72 CA-MRSA-IV, ST398 LA-MRSA-V, ST541 LA-MRSA-V, ST188 LA-MRSA-IV, and ST692 LA-MRSA-V. Phenotypic characteristics often involved in cathelicidin resistance, such as net surface positive charge, carotenoid production, and hydrogen peroxide susceptibility were also determined in the MRSA strains. Human- and animal-type MRSA strains exhibited clonotype-specific resistance profiles to LL-37, PMAP-36, or CATH-2, indicating the potential role of cathelicidin resistance in the adaptation and colonization of human and animal hosts. The ST5 HA-MRSA isolates showed enhanced resistance to all three cathelicidins and hydrogen peroxide than ST72 CA-MRSA isolates by implementing increased surface positive charge and carotenoid production. In contrast, LA-MRSA strains employed mechanisms independent of surface charge regulation and carotenoid production for cathelicidin resistance. These results suggest that human- and livestock-derived MRSA strains use different strategies to counteract the bactericidal action of cathelicidins during the colonization of their respective host species.

Robot swarm networking systems (RSNS) exhibit complex emergent behavior by using local control laws based on spatial information from nearby environment and adjacent robot agents. The consensus behavior of the RSNS depends on a set of parameters of robot agent algorithms or system parameters for their operation, issued mainly by the operator. The challenge in the RSNS is developing techniques for the operator to interact with the RSNS in order to make system behavior adaptive to changes in system configuration and for operator commands without having to handle them individually. Another challenge is saving energy consumption over the robot agents in the RSNS by reducing the number of information exchange between robot agents when the system configuration is spread out the network from the operator. To address these issues, this paper presents an energy-efficient control approach for system configuration propagation with self-triggering control. The proposed method controls the RSNS operation by indirectly propagating the system configuration within the framework of local rules. Moreover, a self-triggered propagation model is designed according to the convergence rate of configuration propagation in order to save and to balance energy consumption among robot agents in the RSNS. This model is then extended to an optimal timing control, where the operator determines its next input time without having to keep track of all the states of robot agents. Theoretical analysis and simulation results are performed to demonstrate the superiority of the proposed method.

ABSTRACT: Colonization of food-producing animals by antimicrobial-resistant Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), has become a serious public health problem worldwide. In the current study, clonal diversities of livestock-associated S. aureus isolates collected from broiler farms, slaughterhouses, and retail chicken meat were examined. Two-hundred S. aureus isolates (43 MRSA and 157 methicillin-susceptible S. aureus [MSSA] isolates) were analyzed to determine 1) the genotypes of the isolates (multilocus sequence, agr, and spa types), 2) the methicillin resistance phenotype and staphylococcal cassette chromosome mec (SCCmec) types, 3) the antimicrobial resistance profiles, and 4) the mutational changes in gyrA, gyrB, parC, and parE in fluoroquinolone-resistant isolates. Fifteen different sequence types (STs) of MSSA strains displaying a relatively high degree of genetic diversity were detected in broiler farms, slaughterhouses, and retail chicken meat. In contrast to MSSA, 2 dominant genetic lineages of MRSA (ST692-SCCmecV with t2249 spa type, and ST188-SCCmecIVa with spa type t189) were found in healthy broilers. The high prevalence of ST692 and ST188 in healthy broilers is associated with high levels of multiple antimicrobial-resistance phenotypes, particularly fluoroquinolone resistance. All fluoroquinolone-resistant isolates carried double point mutations in gyrA (S84L) and parC (S80F), regardless of STs or methicillin resistance. Notably, only the ST188 lineage carried an additional third mutation in gyrB (D494N), correlating with enhanced ciprofloxacin minimum inhibitory concentration values versus the strains with double mutations. These results provide important insights into the genetic diversity of antimicrobial-resistant S. aureus strains associated with the chicken meat production chain, including healthy broilers, in Korea.

Objective The present study aimed to investigate the occurrence and species of coagulase-positive staphylococci (CoPS) and coagulase-negative staphylococci (CoNS) in retail pork meat samples collected during nationwide monitoring. The staphylococcal isolates were characterized for antimicrobial and zinc chloride resistance and enterotoxigenic potential. Methods A total of 260 pre-packaged pork meat samples were collected from 35 retail markets in 8 provinces in Korea for isolation of staphylococci. Antimicrobial and zinc chloride resistance phenotypes, and genes associated with the resistance phenotypes were determined on the isolates. Furthermore, the presence and distribution of 19 staphylococcal enterotoxin (SE) genes and enterotoxin-like genes among the pork-associated staphylococci were determined by multiplex polymerase chain reaction-based assays using the specific primer sets. Results A total of 29 staphylococcal strains (29/260, 11.1%) were isolated from samples of retail pork meat, 24 (83%) of which were CoNS. The four CoNS species identified were S. saprophyticus (n = 16, 55%), S. sciuri (n = 3, 10%), S. warneri (n = 3, 10%), and S. epidermidis (n = 2, 7%). Among the 29 isolates, four methicillin-resistant CoNS (MR-CoNS; three S. sciuri and one S. epidermidis) and one methicillin-resistant CoPS (MR-CoPS; one S. aureus) were identified. In addition, a relatively high level of tetracycline (TET) resistance (52%) was confirmed in CoNS, along with a predominant distribution of tet(K). The most prevalent SEs were sep (45%), and sen (28%), which were carried by 81% of S. saprophyticus. Conclusion These findings suggest that CoNS, especially S. saprophyticus strains, in raw pork meat could be a potential risk factor for staphylococcal food poisoning (SFP), and therefore, requires further investigation to elucidate the role of SEls in SFP and virulence of the pathogen. Our results also suggest that CoNS from raw pork meat may act as a source for transmission of antimicrobial resistance genes such as staphylococcal cassette chromosome mec and tet(K).

Purpose Hysteroscopy can be used both to diagnose and to treat intrauterine pathologies. It is well known that hysteroscopy helps to improve reproductive outcomes by treating intrauterine pathologies. However, it is uncertain whether hysteroscopy is helpful in the absence of intrauterine pathologies. This study aimed to confirm whether hysteroscopy improves the reproductive outcomes of infertile women without intrauterine pathologies. Methods We conducted a systematic review of 11 studies retrieved from Ovid-MEDLINE, Ovid-Embase, and the Cochrane Library. Two independent investigators extracted the data and used risk-of-bias tools (RoB 2.0 and ROBINS-I) to assess their quality. Results Diagnostic hysteroscopy prior to in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) was associated with a higher clinical pregnancy rate (CPR) and live birth rate (LBR) than non-hysteroscopy in patients with recurrent implantation failure (RIF) (odds ratio, 1.79 and 1.46; 95% confidence interval, 1.40–2.30 and 1.08–1.97 for CPR and LBR, respectively) while hysteroscopy prior to first IVF was ineffective. The overall meta-analysis of LBR showed statistically significant findings for RIF, but a subgroup analysis showed effects only in prospective cohorts (odds ratio, 1.40 and 1.47; 95% confidence interval, 0.62–3.16 and 1.04–2.07 for randomized controlled trials and prospective cohorts, respectively). Therefore, the LBR should be interpreted carefully and further research is needed. Conclusion Although further research is warranted, hysteroscopy may be considered as a diagnostic and treatment option for infertile women who have experienced RIF regardless of intrauterine pathologies. This finding enables nurses to educate and support infertile women with RIF prior to IVF/ICSI.

Abstract A subset of glioblastomas (GBMs) harbors potentially druggable oncogenic FGFR3-TACC3 (F3T3) fusions. However, their associated molecular and clinical features are poorly understood. Here we analyze the frequency of F3T3-fusion positivity, its associated genetic and methylation profiles, and its impact on survival in 906 IDH-wildtype GBM patients. We establish an F3T3 prevalence of 4.1% and delineate its associations with cancer signaling pathway alterations. F3T3-positive GBMs had lower tumor mutational and copy-number alteration burdens than F3T3-wildtype GBMs. Although F3T3 fusions were predominantly mutually exclusive with other oncogenic RTK pathway alterations, they did rarely co-occur with EGFR amplification. They were less likely to harbor TP53 alterations. By methylation profiling, they were more likely to be assigned the mesenchymal or RTK II subclass. Despite being older at diagnosis and having similar frequencies of MGMT promoter hypermethylation, patients with F3T3-positive GBMs lived about 8 months longer than those with F3T3-wildtype tumors. While consistent with IDH-wildtype GBM, F3T3-positive GBMs exhibit distinct biological features, underscoring the importance of pursuing molecular studies prior to clinical trial enrollment and targeted treatment.

Abstract Methicillin-resistant Staphylococcus aureus (MRSA) strains are distinct from general Staphylococcus strains with respect to the composition of the membrane, ability to form a thicker biofilm, and, importantly, ability to modify the target of antibiotics to evade their activity. The agr gene is an accessory global regulator of gram-positive bacteria that governs virulence or resistant mechanisms and therefore an important target for the control of resistant strains. However, the mechanism by which agr impacts resistance to β-lactam antibiotics remains unclear. In the present study, we found the Δagr mutant strain having higher resistance to high concentrations of β-lactam antibiotics such as oxacillin and ampicillin. To determine the influence of variation in the microenvironment of cells between the parental and mutant strains, fatty acid analysis of the supernatant, total lipids, and phospholipid fatty acids were compared. The Δagr mutant strain tended to produce fewer fatty acids and retained lower amounts of C16, C18 fatty acids in the supernatant. Phospholipid analysis showed a dramatic increase in the hydrophobic longer-chain fatty acids in the membrane. To target membrane, we applied several surfactants and found that sorbitan monolaurate (Span20) had a synergistic effect with oxacillin by decreasing biofilm formation and growth. These findings indicate that agr deletion allows for MRSA to resist antibiotics via several changes including constant expression of mecA, fatty acid metabolism, and biofilm thickening.

Lactiplantibacillus plantarum PMO 08 has been used as a probiotic starter culture for plant-based fermented beverages, with various health-promoting effects such as cholesterol-lowering and anti-inflammatory activities. This study aimed to analyze the genome sequence of Lp. plantarum PMO 08 and identify its safety and probiotic characteristics at the genomic level. For this, complete genome sequencing was conducted to investigate the genes associated with risk and probiotic characteristics by using Pacbio combined with Illumina HiSeq. This bacterial strain has one circular chromosome of 3,247,789 bp with 44.5% G + C content and two plasmids of 50,296 bp with 39.0% G + C content and 19,592 bp with 40.5% G + C content. Orthologous average nucleotide identity analysis showed that PMO 08 belongs to the Lp. plantarum group with 99.14% similarity to Lp. plantarum WCFS1. No deleterious genes were determined in the virulence factor analysis, and no hemolysin activity or secondary bile salt synthesis were detected in vitro test. In the case of antibiotic resistance analysis, PMO 08 was resistant to ampicillin in vitro test, but these genes were not transferable. In addition, the strain showed same carbohydrate utilization with Lp. plantarum WCFS1, except for mannopyranoside, which only our strain can metabolize. The strain also harbors a gene for inositol monophosphatase family protein related with phytate hydrolysis and have several genes for metabolizing various carbohydrate which were rich in plant environment. Furthermore, in probiotic characteristics several genes involved in phenotypes such as acid/bile tolerance, adhesion ability, and oxidative stress response were detected in genome analysis. This study demonstrates that Lp. plantarum PMO 08 harbors several probiotic-related genes (with no deleterious genes) and is a suitable probiotic starter for plant-based fermentation.

The emergence and spread of cfr-mediated resistance to linezolid in staphylococci have become a serious global concern. The acquisition of cfr confers multidrug resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A (PhLOPSA phenotype). However, occurrence of cfr-positive and linezolid-susceptible staphylococci has been identified. To investigate the mechanism underlying linezolid susceptibility in cfr-positive Staphylococcus aureus and non-aureus staphylococci (NAS) isolates from pig farms in Korea. Eleven cfr-positive and linezolid-susceptible staphylococci were analyzed for mutations in domain V of 23S rRNA, ribosomal proteins (L3, L4, and L22), cfr open reading frames (ORFs), and cfr promoter regions. The effect of the cfr mutation (Q148K) on the PhLOPSA phenotype was determined using plasmid constructs expressing either the mutated (cfrQ148K) or nonmutated cfr genes. All 11 (six S. aureus and five NAS) cfr-positive and linezolid-susceptible isolates had a point mutation at position 442 in cfr ORFs (C to A) that resulted in the Q148K mutation. No mutations were detected in 23S rRNA, L3, L4, or L22. The Q148K mutation in Cfr is responsible for phenotypes susceptible to PhLOPSA antimicrobial agents. To our knowledge, this is the first study to report the causal role of a single nucleotide mutation (Q148K) in cfr of S. aureus and NAS isolates in PhLOPSA resistance. Continued nationwide surveillance is necessary to monitor the occurrence and dissemination of mutations in cfr that affect resistance phenotypes in staphylococci of human and animal origin.

Abstract Background DLG2, also known as postsynaptic density protein-93 (PSD-93) or chapsyn-110, is an excitatory postsynaptic scaffolding protein that interacts with synaptic surface receptors and signaling molecules. A recent study has demonstrated that mutations in the DLG2 promoter region are significantly associated with autism spectrum disorder (ASD). Although DLG2 is well known as a schizophrenia-susceptibility gene, the mechanisms that link DLG2 gene disruption with ASD-like behaviors remain unclear. Methods Mice lacking exon 14 of the Dlg2 gene (Dlg2 –/– mice) were used to investigate whether Dlg2 deletion leads to ASD-like behavioral abnormalities. To this end, we performed a battery of behavioral tests assessing locomotion, anxiety, sociability, and repetitive behaviors. In situ hybridization was performed to determine expression levels of Dlg2 mRNA in different mouse brain regions during embryonic and postnatal brain development. We also measured excitatory and inhibitory synaptic currents to determine the impacts of Dlg2 deletion on synaptic transmission in the dorsolateral striatum. Results Dlg2 –/– mice showed hypoactivity in a novel environment. They also exhibited decreased social approach, but normal social novelty recognition, compared with wild-type animals. In addition, Dlg2 –/– mice displayed strong self-grooming, both in home cages and novel environments. Dlg2 mRNA levels in the striatum were heightened until postnatal day 7 in mice, implying potential roles of DLG2 in the development of striatal connectivity. In addition, the frequency of excitatory, but not inhibitory, spontaneous postsynaptic currents in the Dlg2 –/– dorsolateral striatum was significantly reduced. Conclusion These results suggest that homozygous Dlg2 deletion in mice leads to ASD-like behavioral phenotypes, including social deficits and increased repetitive behaviors, as well as reductions in excitatory synaptic input onto dorsolateral spiny projection neurons, implying that the dorsal striatum is one of the brain regions vulnerable to the developmental dysregulation of DLG2.

Inflammatory myofibroblastic tumor (IMT) of the uterus is a rare but aggressive malignancy that is often misdiagnosed. Approximately 50% of uterine IMTs (UMT) harbor rearrangements involving the ALK gene on chromosome 2p23 with subsequent overexpression of the ALK protein. Molecular characterization and wider availability of immunohistochemistry (IHC) and next generation sequencing (NGS) have improved clinical recognition and accurate diagnosis of UMT. The discovery of ALK fusions as a genomic driver led to the FDA approval of ALK inhibitors in ALK-altered lung cancers, but there are limited data to date on the spectrum of ALK fusions or patterns of response and resistance to ALK inhibitors in ALK-altered UMT. In this report we describe the genomic and histopathological characteristics and the response to ALK-targeted therapy in four patients with UMT. In all four patients, clinical activity of ALK inhibition was observed, with durable responses lasting 12 months or more. Moreover, three patients derived benefit from a second-generation ALK inhibitor after progression of disease or intolerance to the first-generation inhibitor crizotinib. Our report advocates for consideration of expanding the current National Comprehensive Cancer Network (NCCN) guidelines to include later-generation ALK inhibitors for the treatment of ALK-rearranged UMTs.

Helicobacter pylori is a gram-negative, microaerophilic, and spiral-shaped bacterium and causes gastrointestinal diseases in human. IL-1β is a representative cytokine produced in innate immune cells and is considered to be a key factor in the development of gastrointestinal malignancies. However, the mechanism of IL-1β production by neutrophils during H. pylori infection is still unknown. We designed this study to identify host and bacterial factors involved in regulation of H. pylori-induced IL-1β production in neutrophils. We found that H. pylori-induced IL-1β production is abolished in NLRP3-, ASC-, and caspase-1/11-deficient neutrophils, suggesting essential role for NLRP3 inflammasome in IL-1β response against H. pylori. Host TLR2, but not TLR4 and Nod2, was also required for transcription of NLRP3 and IL-1β as well as secretion of IL-1β. H. pylori lacking cagL, a key component of the type IV secretion system (T4SS), induced less IL-1β production in neutrophils than did its isogenic WT strain, whereas vacA and ureA were dispensable. Moreover, T4SS was involved in caspase-1 activation and IL-1β maturation in H. pylori-infected neutrophils. We also found that FlaA is essential for H. pylori-mediated IL-1β production in neutrophils, but not dendritic cells. TLR5 and NLRC4 were not required for H. pylori-induced IL-1β production in neutrophils. Instead, bacterial motility is essential for the production of IL-1β in response to H. pylori. In conclusion, our study shows that host TLR2 and NLRP3 inflammasome and bacterial T4SS and motility are essential factors for IL-1β production by neutrophils in response to H. pylori.

Summary: Ataxia-telangiectasia mutated (ATM) is a serine/threonine kinase that coordinates the response to DNA double-strand breaks and oxidative stress. NKX3.1, a prostate-specific transcription factor, was recently shown to directly stimulate ATM kinase activity through its highly conserved homeodomain. Here, we show that other members of the homeodomain family can also regulate ATM kinase activity. We found that six representative homeodomain proteins (NKX3.1, NKX2.2, TTF1, NKX2.5, HOXB7, and CDX2) physically and functionally interact with ATM and with the Mre11-Rad50-Nbs1 (MRN) complex that activates ATM in combination with DNA double-strand breaks. The binding between homeodomain proteins and ATM stimulates oxidation-induced ATM activation in vitro but inhibits ATM kinase activity in the presence of MRN and DNA and in human cells. These findings suggest that many tissue-specific homeodomain proteins may regulate ATM activity during development and differentiation and that this is a unique mechanism for the control of the DNA damage response. : Johnson et al. demonstrate that several members of the homeobox transcription factor family bind directly to the ATM protein kinase and to the MRN complex, inhibiting activation of ATM by DNA double-strand breaks. These results suggest that homeobox proteins may act as tissue-specific regulators of the DNA damage response. Keywords: ATM, DNA damage response, DNA double-strand breaks, homeodomain proteins, MRN

Abstract Hepatitis E virus (HEV) is a zoonotic pathogen commonly considered an important foodborne virus. Pet dogs are important reservoirs of zoonotic agents. In the present study, the seroprevalence of HEV in pet dogs and pet veterinarians were found to be 28.2 and 5.0%, respectively. It remains unclear whether pet veterinarians are at higher risk of HEV transmission. However, pet animals and individuals who have contact with infected animals must be continually monitored for public health concerns.

Non-aureus staphylococci (NAS), including coagulase-negative staphylococci, have emerged as important causes of opportunistic infections in humans and animals and a potential cause of staphylococcal food poisoning. In this study, we investigated (i) the staphylococcal species profiles of NAS in in retail chicken meat, (ii) the phenotypic and genotypic factors associated with antimicrobial resistance in the NAS isolates, and (iii) the prevalence of classical and newer staphylococcal enterotoxin (SE) genes. A total of 58 NAS of nine different species were isolated from retail raw chicken meat samples. The occurrence of multidrug resistance in the NAS, particularly S. agnetis and S. chromogenes, with high resistance rates against tetracycline or fluoroquinolones were confirmed. The tetracycline resistance was associated with the presence of tet(L) in S. chromogenes and S. hyicus or tet(K) in S. saprophyticus. The occurrence of fluoroquinolone resistance in S. agnetis and S. chromogenes was usually associated with mutations in the quinolone resistance determining regions (QRDR) of gyrA and parC. In addition, the frequent presence of SE genes, especially seh, sej, and sep, was detected in S. agnetis and S. chromogenes. Our findings suggest that NAS in raw chicken meat can have potential roles as reservoirs for antimicrobial resistance and enterotoxin genes.

Sequence type (ST) 72 methicillin-resistant Staphylococcus aureus with staphylococcal cassette chromosome mec (SCCmec) type IV (ST72-MRSA-IV) and ST5-MRSA-II are the most significant lineages found in community-associated (CA) and healthcare-associated (HA) environments in Korea, respectively. ST5 HA-MRSA-II tend to display enhanced resistance to host defense-cationic antimicrobial peptides (HD-CAPs) compared to ST72 CA-MRSA-IV and ST72 livestock-associated (LA)-MRSA-IV due to mechanisms involving a higher surface positive charge. Thus, the present study explored the genetic factors contributing to the enhanced HD-CAP resistance phenotype in ST5 MRSA strains. The ST5 HA-MRSA-II strains displayed higher levels of mprF and dltABCD expression compared to the ST72 CA-/LA-MRSA-IV strains. The increase in expression of mprF and dltABCD in ST5 HA-MRSA-II strains was correlated with dysregulation of the upstream transcriptional regulator, graRS. However, single nucleotide polymorphisms (SNPs) within mprF and graRS ORFs were not involved in the enhanced surface positive charge or the altered expression of mprF/dltABCD.