Integration of Vertical Graphene Onto a Tunnelling Cathode for Digital X-Ray Imaging.

As an alternative to thermionic X-ray generators, cold-cathode X-ray tubes are being developed for portable and multichannel tomography. Field emission propagating from needle structures such as carbon nanotubes or Si tips currently dominates related research and development, but various obstacles prevent the widespread of this technology. An old but simple electron emission design is the planar tunnelling cathode using a metal-oxide-semiconductor (MOS) structure, which achieves narrow beam dispersion and low supplying voltage. Directly grown vertical graphene (VG) is employed as the gate electrode of MOS and tests its potential as a new emission source. The emission efficiency of the device is initially ≈1% because of unavoidable fabrication damage during the patterning processes; it drastically improves to >40% after ozone treatment. The resulting emission current obeys the Fowler-Nordheim tunnelling model, and the enhanced emission is attributed to the effective gate thickness reduction by ozone treatment. As a proof-of-concept experiment, a clustered array of 2140 cells is integrated into a system that provides mA-class emission current for X-ray generation. With pulsed digital excitations, X-ray imaging of a chest phantom, demonstrating the feasibility of using a VG MOS electron emission source as a new and innovative X-ray generator is realized.

Emergence of the mobile colistin resistance gene mcr-1 in a Leclercia adecarboxylata strain isolated from wastewater in Seoul.

Colistin is considered the last resort for treating infections caused by multidrug-resistant bacteria. However, the spread of the plasmid-borne colistin-resistance gene mcr-1 has become a public health threat. In this study, we identified mcr-1-harboring Leclercia adecarboxylata strain (WWCOL-134) isolated from wastewater in Seoul. The strain had a colistin MIC value of 2 µg/ml and was resistant to cefotaxime, gentamicin, tetracycline, trimethoprim and sulfamethoxazole. The mcr-1 gene, along with an array of resistance genes, was located on a 236-kb plasmid (pCOL134-1), which contained the typical IncHI2 backbone of reported mcr-1-carrying plasmids, and was transferred to an Escherichia coli strain by conjugation. To the best of our knowledge, this is the first study to report the emergence of mcr-1-harboring Leclercia sp. isolate. Our findings demonstrate the ongoing spread of colistin resistance among Enterobacterales species, emphasizing the need for surveillance of antimicrobial resistance in wastewater environments.

Micro-CT determination of the porosity of two tricalcium silicate sealers applied using three obturation techniques.

PURPOSE: Using X-ray micro-computed tomography (micro-CT), the aim of this study was to measure the porosity of two tricalcium silicate sealers (EndoSequence BC and NeoSealer Flo) applied using three obturation techniques (single-cone, warm-vertical, and cold-lateral) to six single-rooted human teeth. METHODS: Six extracted, single-rooted human teeth were shaped with ProTaper Next rotary files and obturated with EndoSequence BC or NeoSealer Flo sealers and gutta-percha (GP) using one of the three techniques above. Micro-CT was used to map the full length of the canals. Deep learning cross-sectional segmentation was used to analyze image slices of the apical (0-2 mm) and coronal (14-16 mm from the apex) regions (n = 230-261 per tooth) for the areas of GP and sealer, as well as porosity. Median (%) with interquartile range of porosity were calculated , and the results were statistically analyzed with the Kruskal-Wallis test. RESULTS: In the apical region, EndoSequence BC had significantly fewer pores than NeoSealer Flo with the single-cone obturation (% median-interquartile range, IQR: 0.00-1.62) and warm-vertical condensation (5.57-10.32) techniques, whereas in the coronal region, NeoSealer Flo had significantly fewer pores than EndoSequence BC with these two techniques (0.39-5.02) and (0.10-0.19), respectively. There was no significant difference in porosity between the two sealers for the cold-lateral condensation technique in both the apical and coronal regions. CONCLUSION: For optimal obturation, the choice of technique and sealer is critical.

An analysis of variants in TARDBP in the Korean population with amyotrophic lateral sclerosis: comparison with previous data.

The TARDBP gene variant is a known major cause of amyotrophic lateral sclerosis (ALS), with limited reports of Korean patients with ALS harboring the variants in TARDBP. This large cohort study introduces four ALS patients who share the p.M337V variant of the TARDBP, allowing for an investigation of clinical characteristics and prognosis by analyzing previously reported cases with the same variant. From November 2014 to August 2022, participants were recruited from two tertiary hospitals in Seoul, Korea. Clinical characteristics of patients diagnosed with ALS carrying the variant in TARDBP were evaluated. Previous articles demonstrating subjects' characteristics were reviewed. Four patients were identified with the pathogenic missense variant (c.1009A>G; p.M337V) in the TARDBP. The mean age of onset was 55 years old, and none of the patients showed severe cognitive impairment. Sixty-three patients carrying the p.M337V variant in TARDBP from this study and previous reports delineated young age of onset (51.6 years), high frequency of bulbar onset patients (61.9%), and low comorbidity of frontotemporal dementia. This study reveals the presence of pathogenic variant of TARDBP in Korea and emphasizes the importance of genetic screening of the TARDBP gene, in diagnosing ALS and evaluating prognosis among familial and simplex ALS patients in Korea.

Subclinical articulatory changes of vowel parameters in Korean amyotrophic lateral sclerosis patients with perceptually normal voices.

The available quantitative methods for evaluating bulbar dysfunction in patients with amyotrophic lateral sclerosis (ALS) are limited. We aimed to characterize vowel properties in Korean ALS patients, investigate associations between vowel parameters and clinical features of ALS, and analyze subclinical articulatory changes of vowel parameters in those with perceptually normal voices. Forty-three patients with ALS (27 with dysarthria and 16 without dysarthria) and 20 healthy controls were prospectively collected in the study. Dysarthria was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R) speech subscores, with any loss of 4 points indicating the presence of dysarthria. The structured speech samples were recorded and analyzed using Praat software. For three corner vowels (/a/, /i/, and /u/), data on the vowel duration, fundamental frequency, frequencies of the first two formants (F1 and F2), harmonics-to-noise ratio, vowel space area (VSA), and vowel articulation index (VAI) were extracted from the speech samples. Corner vowel durations were significantly longer in ALS patients with dysarthria than in healthy controls. The F1 frequency of /a/, F2 frequencies of /i/ and /u/, the VSA, and the VAI showed significant differences between ALS patients with dysarthria and healthy controls. The area under the curve (AUC) was 0.912. The F1 frequency of /a/ and the VSA were the major determinants for differentiating ALS patients who had not yet developed apparent dysarthria from healthy controls (AUC 0.887). In linear regression analyses, as the ALSFRS-R speech subscore decreased, both the VSA and VAI were reduced. In contrast, vowel durations were found to be rather prolonged. The analyses of vowel parameters provided a useful metric correlated with disease severity for detecting subclinical bulbar dysfunction in ALS patients.

Non-chemotherapy adjuvant agents in TP53 mutant Ewing sarcoma.

Ewing sarcoma (EWS) is a malignant tumor arising in bone or soft tissue that occurs in adolescent and young adult patients as well as adults later in life. Although non-metastatic EWS is typically responsive to treatment when newly diagnosed, relapsed cases have an unmet need for which no standard treatment approach exists. Recent phase III clinical trials for EWS comparing 7 vs 5 chemotherapy drugs have failed to improve survival. To extend the durability of remission for EWS, we investigated 3 non-chemotherapy adjuvant therapy drug candidates to be combined with chemotherapy. The efficacy of these adjuvant drugs was investigated via anchorage-dependent growth assays, anchorage-independent soft-agar colony formation assays and EWS xenograft mouse models. Enoxacin and entinostat were the most effective adjuvant drug in both long-term in vitro and in vivo adjuvant studies. In the context that enoxacin is an FDA-approved antibiotic, and that entinostat is an investigational agent not yet FDA-approved, we propose enoxacin as an adjuvant drug for further preclinical and clinical investigation in EWS patients.

Genotypic shift in rotavirus associated with neonatal outbreaks in Seoul, Korea.

BACKGROUND: Rotavirus group A (RVA) is a causative agent of acute gastroenteritis among young children worldwide, despite the global expansion of rotavirus vaccination. In Korea, although the prevalence of RVA has been reduced among young children owing to vaccination, nosocomial infections still occur among neonates. OBJECTIVES: The aim of this study was to investigate the molecular epidemiology of RVA strains associated with several neonatal outbreaks in Seoul from 2017 to 2020. STUDY DESIGN: Clinical and environmental samples were collected and screened for the presence of RVA using ELISA and PCR targeting VP6, respectively. RVA-positive strains were genotyped via RT-PCR and subsequent sequencing of VP4 and VP7 and were phylogenetically compared with RVA strains from other countries. RESULTS: During 2017-2020, a total of 15 RVA outbreaks occurred at neonatal facilities (six in hospital neonatal wards and nine in postpartum care centers) in Seoul, and only two RVA genotypes were detected: G4P[6] and G8P[6]. G8P[6] emerged in Seoul November 2018 and immediately became the predominant genotype among neonates, at least up to 2020. Phylogenetic analysis revealed that the G8P[6] genotype in this study was closely related to G8P[6] strains first identified in Korea in 2017, but differed from G8P[6] strains detected in Africa. CONCLUSIONS: A novel G8P[6] genotype of RVA strains has emerged and caused outbreaks among neonates in Seoul. Continued surveillance for circulating RVA genotypes is imperative to monitor genotype changes and their potential risks to public health.

Small RNA sequencing of circulating small extracellular vesicles microRNAs in patients with amyotrophic lateral sclerosis.

Dysregulation of microRNAs (miRNA) in small extracellular vesicles (sEV) such as exosomes have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Although circulating cell-free miRNA have been extensively investigated in ALS, sEV-derived miRNAs have not been systemically explored yet. Here, we performed small RNA sequencing analysis of serum sEV and identified 5 differentially expressed miRNA in a discovery cohort of 12 patients and 11 age- and sex-matched healthy controls (fold change > 2, p < 0.05). Two of them (up- and down-regulation of miR-23c and miR192-5p, respectively) were confirmed in a separate validation cohort (18 patients and 15 healthy controls) by droplet digital PCR. Bioinformatic analysis revealed that these two miRNAs interact with distinct sets of target genes and involve biological processes relevant to the pathomechanism of ALS. Our results suggest that circulating sEV from ALS patients have distinct miRNA profiles which may be potentially useful as a biomarker of the disease.

Self-Aligned Liquid Crystals on Anisotropic Nano/Microstructured Lanthanum Yttrium Strontium Oxide Layer.

We propose an efficient alignment method for liquid crystals (LCs). A brush-coating method handles film deposition and LC alignment treatment simultaneously herein, meaning a reduction in the conventional alignment layer treatment process steps. A lanthanum yttrium strontium oxide (LaYSrO) film prepared by the sol-gel process was used for the alignment layer. Topographical details of the brush-coated LaYSrO films (compared with spin-coated films) were investigated by atomic force microscopy. Spin-coated LaYSrO meant that the film formation alone without orientation treatment represented an isotropic surface. On the other hand, the 270 °C-cured brush-coated LaYSrO showed nano/microstructure with directionality. It indicates that brush-hair sweeping induced shearing stress on the sol state of the LaYSrO, which results in surface anisotropy for LC alignment. The uniform LC alignment state was confirmed by polarized optical microscopy and pretilt analysis. The brush-coated LaYSrO shows fine optical transparency compared to plain and indium-tin-oxide coated glasses, and thermal stability up to 150 °C for LC alignment. Competitive electro-optical performances of the brush-coated LaYSrO were verified in a twisted-nematic LC system compared to those of the conventionally used polyimide layer. Consequently, we expect that the brush-coating process can be an innovative technology for LC alignment.

Sensitization of osteosarcoma to irradiation by targeting nuclear FGFR1.

Over the past 25 years, chemotherapy regimens for osteosarcoma have failed to improve the 65-70% long-term survival rate. Radiation therapy is generally ineffective except for palliative care. We here investigated whether osteosarcoma can be sensitized to radiation therapy targeting specific molecules in osteosarcoma. Large-scale RNA sequencing analysis in osteosarcoma tissues and cell lines revealed that FGFR1 is the most frequently expressed receptor tyrosine kinase in osteosarcoma. Nuclear FGFR1 (nFGFR1) was observed by subcellular localization assays. The functional studies using a FGFR1IIIb antibody or small molecule FGFR1 inhibitors showed that nFGFR1, but not membrane-bound FGFR1, induces G2 cell-cycle checkpoint adaptation, cell survival and polyploidy following irradiation in osteosarcoma cells. Further, the activation of nFGFR1 induces Histone H3 phosphorylation at Ser 10 and c-jun/c-fos expression to contribute cell survival rendering radiation resistance. Furthermore, an in vivo mouse study revealed that radiation resistance can be reversed by the inhibition of nFGFR1. Our findings provide insights into the potential role of nFGFR1 to radiation resistance. Thus, we propose nFGFR1 could be a potential therapeutic target or a biomarker to determine which patients might benefit from radiation therapy.

Spatiotemporal neural network with attention mechanism for El Niño forecasts.

To learn spatiotemporal representations and anomaly predictions from geophysical data, we propose STANet, a spatiotemporal neural network with a trainable attention mechanism, and apply it to El Niño predictions for long-lead forecasts. The STANet makes two critical architectural improvements: it learns spatial features globally by expanding the network's receptive field and encodes long-term sequential features with visual attention using a stateful long-short term memory network. The STANet conducts multitask learning of Nino3.4 index prediction and calendar month classification for predicted indices. In a comparison of the proposed STANet performance with the state-of-the-art model, the accuracy of the 12-month forecast lead correlation coefficient was improved by 5.8% and 13% for Nino3.4 index prediction and corresponding temporal classification, respectively. Furthermore, the spatially attentive regions for the strong El Niño events displayed spatial relationships consistent with the revealed precursor for El Niño occurrence, indicating that the proposed STANet provides good understanding of the spatiotemporal behavior of global sea surface temperature and oceanic heat content for El Niño evolution.

ROR activation by Nobiletin enhances antitumor efficacy via suppression of IκB/NF-κB signaling in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by poor response to standard therapies and therefore unfavorable clinical outcomes. Better understanding of TNBC and new therapeutic strategies are urgently needed. ROR nuclear receptors are multifunctional transcription factors with important roles in circadian pathways and other processes including immunity and tumorigenesis. Nobiletin (NOB) is a natural compound known to display anticancer effects, and our previous studies showed that NOB activates RORs to enhance circadian rhythms and promote physiological fitness in mice. Here, we identified several TNBC cell lines being sensitive to NOB, by itself or in combination. Cell and xenograft experiments showed that NOB significantly inhibited TNBC cell proliferation and motility in vitro and in vivo. ROR loss- and gain-of-function studies showed concordant effects of the NOB-ROR axis on MDA-MB-231 cell growth. Mechanistically, we found that NOB activates ROR binding to the ROR response elements (RRE) of the IκBα promoter, and NOB strongly inhibited p65 nuclear translocation. Consistent with transcriptomic analysis indicating cancer and NF-κB signaling as major pathways altered by NOB, p65-inducible expression abolished NOB effects, illustrating a requisite role of NF-κB suppression mediating the anti-TNBC effect of NOB. Finally, in vivo mouse xenograft studies showed that NOB enhanced the antitumor efficacy in mammary fat pad implanted TNBC, as a single agent or in combination with the chemotherapy agent Docetaxel. Together, our study highlights an anti-TNBC mechanism of ROR-NOB via suppression of NF-κB signaling, suggesting novel preventive and chemotherapeutic strategies against this devastating disease.

Improving the robustness of a catalyzed hairpin assembly with a three-arm nanostructure for nonenzymatic signal amplification.

Kinetically trapped hairpin DNA has great potential to dynamically build nanostructures, which can be initiated by sequence-specific nucleic acids. The branched junction, which has a multi-arm structure, is a representative nanostructure of DNA. In this study, we report a nonenzymatic and isothermal signal amplification accompanied by building a 3-arm structure based on a catalyzed hairpin DNA assembly (3-CHA). We improved the signal-to-background ratio of the 3-CHA by suppressing the leakage pathway of 3-CHA, thus eliminating unfavorable reaction sites exposed in the single-stranded region of hairpin DNAs. Background and amplified signals were analyzed with gel electrophoresis and real-time fluorescence monitoring. The limit of detection of the developed 3-CHA was estimated to be 29.3 pM for catalyst DNA at room temperature. Supported by the reduced leakage signal, the implemented 3-CHA showed great potential for detecting low concentrations of target DNA.

MDMA and memory, addiction, and depression: dose-effect analysis.

RATIONALE: ±3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug that shows substantial promise as a psychotherapeutic agent. Still, there is some concern regarding its behavioral toxicity, and its dose-effect relationship is poorly understood. We previously explored the role of dose in the cognitive effects of MDMA in a systematic review of existing literature and found no evidence in animals that MDMA impairs memory at low doses (< 3 mg/kg) but mixed results at high doses (≥ 3 mg/kg). Since this review comprised mostly of single-dose studies and an assortment of methodologies, an empirical dose-ranging study on this topic is warranted. OBJECTIVES: The current study aims to evaluate the conclusion from our systematic review that 3 mg/kg may be the threshold for MDMA-induced amnesia, and to further understand the dose-effect relationship of MDMA on behavioral assays of memory, addiction, and depression. METHODS: We systematically examined the effects of 0.01 to 10 mg/kg MDMA on Pavlovian fear conditioning; behavioral sensitization, conditioned place preference, and conditioned responding; and the Porsolt forced swim test in mice. RESULTS: High doses of MDMA (≥ 3 mg/kg) produced amnesia of fear conditioning memory, some evidence of an addictive potential, and antidepressant effects, while low doses of MDMA (≤ 1 mg/kg) had no effect on these behaviors. CONCLUSIONS: The present dose-ranging study provides further evidence that 3 mg/kg is the threshold for MDMA-induced amnesia. These findings, in addition to our systematic review, demonstrate that careful selection of MDMA dose is critical. High doses (≥ 3 mg/kg) should likely be avoided due to evidence that they can produce amnesia and addiction. Conversely, there is little evidence to suggest that low doses, which are usually administered in clinical studies (approximately 1-2 mg/kg), will lead to these same adverse effects. Ultra-low doses (< 1 mg/kg) are likely even safer and should be investigated for therapeutic effects in future studies.

SMARCA4 biology in alveolar rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar subtype (ARMS) has the poorest prognosis and represents the greatest unmet medical need for RMS. Emerging evidence supports the role of epigenetic dysregulation in RMS. Here we show that SMARCA4/BRG1, an ATP-dependent chromatin remodeling enzyme of the SWI/SNF complex, is prominently expressed in primary tumors from ARMS patients and cell cultures. Our validation studies for a CRISPR screen of 400 epigenetic targets identified SMARCA4 as a unique factor for long-term (but not short-term) tumor cell survival in ARMS. A SMARCA4/SMARCA2 protein degrader (ACBI-1) demonstrated similar long-term tumor cell dependence in vitro and in vivo. These results credential SMARCA4 as a tumor cell dependency factor and a therapeutic target in ARMS.

Application of Polynomial Regression Model for Joint Stiffness.

Quasi-stiffness (joint stiffness) is often used to characterize leg properties during athletic and other activities and has been reported by a single slope of angle-moment curve. However, the joint angle-moment relationship of some relationship are not effectively represented by a simple linear regression model. Thus, the purpose of this analysis was to investigate the benefits of utilizing a 2nd order polynomial regression (quadratic) model as compared to the linear model when calculating lower extremity joint stiffness incorporating subdivided eccentric phases. Thirty healthy and active college students performed 15 drop jumps from a 30-cm platform. The eccentric phase was identified as the time from initial foot contact (IC) to the lowest vertical position of the center of mass and subdivided into the loading and attenuation phases, separated by the peak vertical ground reaction force. Lower extremity joint stiffnesses (hip, knee, and ankle) for the loading and attenuation phases were calculated using a linear and quadratic model. Multiple 2 by 2 repeated measures ANOVAs were performed. In the post-hoc analyses, the quadratic model had greater goodness-of-fit (r 2 and RMSE) than the linear model (p < .05) for all joints. The quadratic model revealed differences between the loading and attenuation phases for both hip (p = .001) and knee stiffness (p < .001). These results suggest that the quadratic model is more representative of the angle-moment relationship while subdividing the eccentric phase of a drop jump into the loading and attenuation phases.