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BackgroundSinonasal squamous cell carcinoma (SCC) is a rare disease entity, comprising less than 5% of malignancies of the head and neck. While surgery is the primary treatment approach, neoadjuvant and adjuvant therapies play crucial roles in enhancing the prognosis of patients undergoing treatment with the goal of cure. In this study, we aimed to explore the treatment outcomes of neoadjuvant chemotherapy (NAC) in patients with locally advanced sinonasal SCC.MethodsMedical records of patients diagnosed of locally advanced (cT3-4b, N0-3) sinonasal SCC treated with a definitive aim between January 2005 and March 2023 were retrospectively reviewed. Patients were categorized into the following groups based on the initial treatment: NAC followed by surgery, NAC followed by concurrent chemoradiotherapy (CCRT), definitive CCRT, or upfront surgery. Initial treatment plan was decided by a multidisciplinary team. Primary endpoint was overall survival (OS) and objective response rate, and secondary endpoints were progression free survival (PFS), cumulative incidence of local and distant failures, and treatment-related toxicity. The treatment response was assessed according to the RECIST criteria.ResultsTotal 126 patients were included, and the median follow-up period was 25.6 months. The objective response rate to NAC was 48.2%. The subsequent resection rate was 70%, 42.9%, and 16.7% for patients with stage T3, T4a, and T4b disease, respectively. Two-year progression-free survival did not differ significantly between the NAC followed by surgery and upfront surgery groups (53.6% vs. 60.6%, P = 0.615) or between the NAC followed by CCRT and definitive CCRT groups (26.7% vs. 37.4%, P = 0.506).ConclusionNAC may be a valuable treatment option for patients with locally advanced sinonasal SCC, as it provides an opportunity for curative surgery and exhibits non-inferior oncological outcomes compared with upfront definitive local treatments.

Background/Aims: To investigate a reported outbreak of presumed hepatitis E virus (HEV) infection in a Korean food manufacturing facility and to explore the association between anti-HEV immunoglobulin M (IgM) positivity and coronavirus disease 2019 (COVID-19) infection or vaccination.Methods: Twenty-four cases of anti-HEV IgM positivity were reported among 646 workers at the facility in 2022. An epidemiological investigation was conducted, comprising HEV-RNA testing of blood and environmental samples, analysis of group meal records, and an association between anti-HEV IgM positivity and confirmed COVID-19 infection or vaccination.Results: All 24 patients were asymptomatic, with cases spread sporadically across the facility. HEV RNA was not detected in the serum or environmental samples. Four out of 340 meals (1.2%) showed a significantly higher proportion of anti-HEV positivity in each meal intake group than in the non-intake group on certain days. Although the cumulative rate of COVID-19 infection showed no difference, the anti-HEV IgM positive group showed significantly higher proportions of >2 doses of COVID-19 vaccination (83.3% vs 48.7%, p=0.021), vaccination within 90 days (45.8% vs 19.7%, p=0.008), and having the Moderna vaccine administered as the last vaccine (75.0% vs 14.5%, p

Background The use of helmet treatment for positional plagiocephaly has increased recently; however, its effect is unknown in Korea. Purpose This study aimed to investigate the effectiveness of helmet therapy and identify its influencing factors. Methods Ninety pediatric patients diagnosed with moderate to severe positional plagiocephaly received helmet therapy. Severity of moderate to severe positional plagiocephaly was defined as cranial vault asymmetry (CVA) >10 mm or CVA index (CVAI) >6%. Patients were categorized by age, severity, and daily helmet wear. Multiple regression analysis controlled for factors like sex and prematurity. Treatment success was assessed by comparing pre/post-helmet theray CVA and CVAI, considering normalization or decrease to mild plagiocephaly (CVA ≤10 mm or CVAI ≤6%). Results A total of 90 participants were enrolled (mean age, 5.6±1.6 months; male, 53 [58.9%]). The mean helmet therapy duration was 6.4±2.7 months, while the mean daily wear time was 18.4±2.7 hours. Among the 90 patients, 66 (73.3%) had moderate disease and 24 (26.7%) had severe disease. The mean CVA and CVAI decreased by 6.3±2.7 mm and 4.3%±1.8% after versus before treatment (P

Fibroblast growth factor 23 (FGF23) is a member of endocrine FGF family, along with FGF15/19 and FGF21. Recent reports showed that under pathological conditions, liver produces FGF23, although the role of hepatic FGF23 remains nebulous. Here, we investigated the role of hepatic FGF23 in alcoholic liver disease (ALD) and delineated the underlying molecular mechanism. FGF23 expression was compared in livers from alcoholic hepatitis patients and healthy controls. The role of FGF23 was examined in hepatocyte-specific knock-out (LKO) mice of cannabinoid receptor type 1 (CB1R), estrogen related receptor γ (ERRγ), or FGF23. Animals were fed with an alcohol-containing liquid diet alone or in combination with ERRγ inverse agonist. FGF23 is mainly expressed in hepatocytes in the human liver, and it is upregulated in ALD patients. In mice, chronic alcohol feeding leads to liver damage and induced FGF23 in liver, but not in other organs. FGF23 is transcriptionally regulated by ERRγ in response to alcohol-mediated activation of the CB1R. Alcohol induced upregulation of hepatic FGF23 and plasma FGF23 levels is lost in ERRγ-LKO mice, and an inverse agonist mediated inhibition of ERRγ transactivation significantly improved alcoholic liver damage. Moreover, hepatic CYP2E1 induction in response to alcohol is FGF23 dependent. In line, FGF23-LKO mice display decreased hepatic CYP2E1 expression and improved ALD through reduced hepatocyte apoptosis and oxidative stress. We recognized CBIR-ERRγ-FGF23 axis in facilitating ALD pathology through hepatic CYP2E1 induction. Thus, we propose FGF23 as a potential therapeutic target to treat ALD.

Abstract NA4/NA6, an intermediate degradation product of β-agarase, is a high value-added product with anticancer, anti-obesity, and anti-diabetic effects. Therefore, a method that enables the efficient production of NA4/NA6 would be useful from economic and medical perspectives. In this study, we aimed to generate a Streptomyces coelicolor A3(2) mutant M22-2C43 that produces NA4/NA6 as a final product; this method serves as a more efficient alternative to the enzymatic conversion of β-agarase for the generation of these products. The M22-2C43 strain was generated through two rounds of mutagenesis and screening for increased β-agarase activity and effective production of NA4/NA6. We assembled the complete genomes of two mutants, M22 and M22-2C43, which were identified following a two-round screening. Large and small genetic changes were found in these two mutants, including the loss of two plasmids present in wild-type S. coelicolor A3(2) and chromosome circularization of mutant M22-2C43. These findings suggest that mutant M22-2C43 can produce NA4/NA6 as a degradation product due to functional inactivation of the dagB gene through a point mutation (G474A), ultimately preventing further degradation of NA4/NA6 to NA2. To our knowledge, this is the first report of a microbial strain that can effectively produce NA4/NA6 as the main degradation product of β-agarase, opening the door for the use of this species for the large-scale production of this valuable product.

Abstract Background Efforts have been made to investigate the role of salvage radiotherapy (RT) in treating recurrent ovarian cancer (ROC). Stereotactic ablative radiation therapy (SABR) is a state-of-the-art therapy that uses intensity modulation to increase the fractional dose, decrease the number of fractions, and target tumors with high precision. Methods The SABR-ROC trial is a phase 3, multicenter, randomized, prospective study to evaluate whether the addition of SABR to the standard of care significantly improves the 3-year overall survival (OS) of patients with ROC. Patients who have completed the standard treatment for primary epithelial ovarian cancer are eligible. In addition, patients with number of metastases ≤ 10 and maximum diameter of each metastatic site of gross tumor ≤ 5 cm are allowed. Randomization will be stratified by (1) No. of the following clinical factors met, platinum sensitivity, absence of ascites, normal level of CA125, and ECOG performance status of 0–1; 0–3 vs. 4; (2) site of recurrence; with vs. without lymph nodes; and (3) PARP inhibitor; use vs. non-use. The target number of patients to be enrolled in this study is 270. Participants will be randomized in a 1:2 ratio. Participants in Arm 2 will receive SABR for recurrent lesions clearly identified in imaging tests as well as the standard of care (Arm 1) based on treatment guidelines and decisions made in multidisciplinary discussions. The RT fraction number can range from 1 to 10, and the accepted dose range is 16–45 Gy. The RT Quality Assurance (QA) program consists of a three-tiered system: general credentialing, trial-specific credentialing, and individual case reviews. Discussion SABR appears to be preferable as it does not interfere with the schedule of systemic treatment by minimizing the elapsed days of RT. The synergistic effect between systemic treatment and SABR is expected to reduce the tumor burden by eradicating gross tumors identified through imaging with SABR and controlling microscopic cancer with systemic treatment. It might also be beneficial for quality-of-life preservation in older adults or heavily treated patients. Trial registration This trial was registered at ClinicalTrials.gov (NCT05444270) on June 29th, 2022.

Dermacoccus barathri is the first reported pathogen within the Dermacoccus genus to cause a catheter-related bloodstream infection, which occurred in 2015. In this study, the complete genome assembly of Dermacoccus barathri was constructed, and the complete genome of Dermacoccus barathri FBCC-B549 consists of a single chromosome (3,137,745 bp) without plasmids. The constructed genome of D. barathri was compared with those of two closely related species within the Dermacoccus genus. D. barathri exhibited a pattern similar to Dermacoccus abyssi in terms of gene clusters and synteny analysis. Contrary to previous studies, biosynthetic gene cluster (BGC) analysis for predicting secondary metabolites revealed the presence of the LAP biosynthesis pathway in the complete genome of D. barathri, predicting the potential synthesis of the secondary metabolite plantazolicin. Furthermore, an analysis to investigate the potential pathogenicity of D. barathri did not reveal any antibiotic resistance genes; however, nine virulence factors were identified in the Virulence Factor Database (VFDB). According to these matching results in the VFDB, despite identifying a few factors involved in biofilm formation, further research is required to determine the actual impact of D. barathri on pathogenicity. The complete genome of D. barathri is expected to serve as a valuable resource for future studies on D. barathri, which currently lack sufficient genomic sequence information.

BackgroundThe outbreak of SARS-CoV-2 in 2019 has necessitated the rapid and accurate detection of COVID-19 to manage patients effectively and implement public health measures. Artificial intelligence (AI) models analyzing cough sounds have emerged as promising tools for large-scale screening and early identification of potential cases. ObjectiveThis study aimed to investigate the efficacy of using cough sounds as a diagnostic tool for COVID-19, considering the unique acoustic features that differentiate positive and negative cases. We investigated whether an AI model trained on cough sound recordings from specific periods, especially the early stages of the COVID-19 pandemic, were applicable to the ongoing situation with persistent variants. MethodsWe used cough sound recordings from 3 data sets (Cambridge, Coswara, and Virufy) representing different stages of the pandemic and variants. Our AI model was trained using the Cambridge data set with subsequent evaluation against all data sets. The performance was analyzed based on the area under the receiver operating curve (AUC) across different data measurement periods and COVID-19 variants. ResultsThe AI model demonstrated a high AUC when tested with the Cambridge data set, indicative of its initial effectiveness. However, the performance varied significantly with other data sets, particularly in detecting later variants such as Delta and Omicron, with a marked decline in AUC observed for the latter. These results highlight the challenges in maintaining the efficacy of AI models against the backdrop of an evolving virus. ConclusionsWhile AI models analyzing cough sounds offer a promising noninvasive and rapid screening method for COVID-19, their effectiveness is challenged by the emergence of new virus variants. Ongoing research and adaptations in AI methodologies are crucial to address these limitations. The adaptability of AI models to evolve with the virus underscores their potential as a foundational technology for not only the current pandemic but also future outbreaks, contributing to a more agile and resilient global health infrastructure.

Virtual reality (VR) offers a forum for a person to immerse themselves in an artificial world. Despite the emergence of VR as a teaching tool, a strong base to understand the pedagogical impact of VR within post-secondary education is absent. Furthermore, there is minimal literature on how VR can be used pedagogically with medical and rehabilitation professional students. This pilot research project sought to answer “how do students perceive that VR should be used within occupational therapy curricula after trialling a variety of educational modules?” Study participants were Masters of Occupational Therapy Students who trialed four different educational modules using four different technological solutions. After each trial they completed a questionnaire specific to the learning and then completed an overall survey about how VR should be considered for future use in the curriculum. Findings showcased that students preferred a higher level of immersion and interaction. They showed less preference for the lower technological and less immersive learning opportunities. Students shared that they would welcome VR solutions to learn about assessment, anatomy and musculoskeletal function, neuroanatomy and neurological foundations and for cases as a preparation for clinical fieldwork experiences. Future research is required to evaluate the impact of a larger scale roll out of specific learning approaches.

IntroductionWe analyzed daily pre-treatment- (PRE) and real-time motion monitoring- (MM) MRI scans of patients receiving definitive prostate radiotherapy (RT) with 1.5 T MRI guidance to assess interfractional and intrafractional variability of the prostate and suggest optimal planning target volume (PTV) margin.Materials and methodsRigid registration between PRE-MRI and planning CT images based on the pelvic bone and prostate anatomy were performed. Interfractional setup margin (SM) and interobserver variability (IO) were assessed by comparing the centroid values of prostate contours delineated on PRE-MRIs. MM-MRIs were used for internal margin (IM) assessment, and PTV margin was calculated using the van Herk formula.ResultsWe delineated 400 prostate contours on PRE-MRI images. SM was 0.57 ± 0.42, 2.45 ± 1.98, and 2.28 ± 2.08 mm in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions, respectively, after bone localization and 0.76 ± 0.57, 1.89 ± 1.60, and 2.02 ± 1.79 mm in the LR, AP, and SI directions, respectively, after prostate localization. IO was 1.06 ± 0.58, 2.32 ± 1.08, and 3.30 ± 1.85 mm in the LR, AP, and SI directions, respectively, after bone localization and 1.11 ± 0.55, 2.13 ± 1.07, and 3.53 ± 1.65 mm in the LR, AP, and SI directions, respectively, after prostate localization. Average IM was 2.12 ± 0.86, 2.24 ± 1.07, and 2.84 ± 0.88 mm in the LR, AP, and SI directions, respectively. Calculated PTV margin was 2.21, 5.16, and 5.40 mm in the LR, AP, and SI directions, respectively.ConclusionsMovements in the SI direction were the largest source of variability in definitive prostate RT, and interobserver variability was a non-negligible source of margin. The optimal PTV margin should also consider the internal margin.

Recently, the superiority of atezolizumab plus bevacizumab (AteBeva) over sorafenib was proven in the IMbrave150 trial, and AteBeva became the first-line systemic treatment for untreated, unresectable hepatocellular carcinoma (HCC). While the results are encouraging, more than half of patients with advanced HCC are still being treated in a palliative setting. Radiotherapy (RT) is known to induce immunogenic effects that may enhance the therapeutic efficacy of immune checkpoint inhibitors. Herein, we report the case of a patient with advanced HCC with massive portal vein tumor thrombosis treated with a combination of RT and AteBeva, who showed near complete response in tumor thrombosis and favorable response to HCC. Although this is a rare case, it shows the importance of reducing the tumor burden via RT to combination immunotherapy in patients with advanced HCC.

Abstract Two-stage tissue expander/implant (TE/I) and deep inferior epigastric perforator (DIEP) flaps are the two main pillars of breast reconstruction. This study aimed to conduct a longitudinal analysis of long-term outcomes after immediate DIEP- and TE/I-based reconstruction. This retrospective cohort study included patients with breast cancer who underwent immediate DIEP- or TE/I-based reconstruction between 2012 and 2017. The cumulative incidence of major complications, defined as unplanned reoperation/readmission due to complications, was analyzed by the reconstruction modality and its independent association. In total, 1,474 cases (1,162 TE/I and 312 DIEP cases) were analyzed, with a median follow-up of 58 months. The 5-year cumulative incidence of major complications was significantly higher in the TE/I group (10.3% vs. 4.7%). On the multivariable analyses, the use of DIEP flap was associated with a significantly reduced risk of major complications compared to that of TE/I. A more prominent association was observed in the analysis of patients who received adjuvant radiotherapy. Restricting analysis to those who received adjuvant chemotherapy revealed no differences between the two groups. The rate of reoperation/readmission for improving aesthetic outcomes was similar in the two groups. Long-term risks for unexpected reoperation/readmission may differ between DIEP- and TE/I-based immediate reconstruction.

Managing building defects in the residential environment is an important social issue in South Korea. Therefore, most South Korean construction companies devote a large amount of human resources and economic costs in managing such defects. This paper proposes a machine learning approach for investigating whether a specific defect can be autonomously categorized into one of the categories of repair tasks. To this end, we employed a dataset of 310,044 defect cases (from 656,266 validated cases of 717,550 total collected cases). Three machine learning classifiers (support vector machine, random forest, and logistic regression) with three word embedding methods (bag-of-words, term frequency-inverse document frequency, and Word2Vec) were employed for the classification tasks. The highest yielded results showed more than 99% accuracy, precision, recall, and F1-scores for the random forest classifier with the Word2Vec embedding. Finally, based on these findings, the implications and limitations of this study are discussed. Representatively, the findings of this research can improve the defect management effectiveness of the apartment construction industry in South Korea. Moreover, to contribute to future research, we have made the dataset publicly available.

Background Excessive proliferation and migration of vascular smooth muscle cells (VSMCs), which contributes to the development of occlusive vascular diseases, requires elevated mitochondrial oxidative phosphorylation to meet the increased requirements for energy and anabolic precursors. Therefore, therapeutic strategies based on blockade of mitochondrial oxidative phosphorylation are considered promising for treatment of occlusive vascular diseases. Here, we investigated whether DN200434, an orally available estrogen receptor-related gamma inverse agonist, inhibits proliferation and migration of VSMCs and neointima formation by suppressing mitochondrial oxidative phosphorylation. Methods VSMCs were isolated from the thoracic aortas of 4-week-old Sprague-Dawley rats. Oxidative phosphorylation and the cell cycle were analyzed in fetal bovine serum (FBS)- or platelet-derived growth factor (PDGF)-stimulated VSMCs using a Seahorse XF-24 analyzer and flow cytometry, respectively. A model of neointimal hyperplasia was generated by ligating the left common carotid artery in male C57BL/6J mice. Results DN200434 inhibited mitochondrial respiration and mammalian target of rapamycin complex 1 activity and consequently suppressed FBS- or PDGF-stimulated proliferation and migration of VSMCs and cell cycle progression. Furthermore, DN200434 reduced carotid artery ligation-induced neointima formation in mice. Conclusion Our data suggest that DN200434 is a therapeutic option to prevent the progression of atherosclerosis.

Background and purpose: Stereotactic ablative radiotherapy (SABR) is popularly used to treat bone metastasis. Despite its efficacy, adverse events, including vertebral compression fracture (VCF), are frequently observed. Here, we investigated VCF risk after SABR for oligometastatic vertebral bone metastasis from hepatocellular carcinoma. Materials and methods: A total of 84 patients with 144 metastatic bone lesions treated at three institutions between 2009 and 2019 were retrospectively reviewed. The primary endpoint was VCF development, either new or progression of a pre-existing VCF. VCFs were assessed using the spinal instability neoplastic score (SINS). Results: Among 144 spinal segments, 26 (18%) had pre-existing VCF and 90 (63%) had soft tissue extension. The median biologically effective dose (BED) was 76.8 Gy. VCF developed in 14 (12%) of 118 VCF-naïve patients and progressed in 20 of the 26 with pre-existing VCF. The median time to VCF development was 6 months (range, 1–12 months). The cumulative incidence of VCF at 12 months with SINS class I, II and III was 0%, 26% and 83%, respectively (p

Abstract Over the past decades, accumulating evidences have highlighted the gut microbiota as a key player in the brain functioning via microbiota–gut–brain axis, and accordingly, the beneficial role of several probiotic strains in cognitive ability also have been actively investigated. However, the majority of the research have demonstrated the effects against age-related cognitive decline or neurological disease. To this end, we aimed to investigate lactic acid bacteria strains having beneficial effects on the cognitive function of healthy young mice and elucidate underlying characteristics by carrying out nanopore sequencing-based genomics and metagenomics analysis. 8-week consumption of Streptococcus thermophilus EG007 demonstrated marked enhancements in behavior tests assessing short-term spatial and non-spatial learning and memory. It was revealed that EG007 possessed genes encoding various metabolites beneficial for a health condition in many aspects, including gamma-aminobutyric acid producing system, a neurotransmitter associated with mood and stress response. Also, by utilizing 16S–23S rRNA operon as a taxonomic marker, we identified more accurate species-level compositional changes in gut microbiota, which was increase of certain species, previously reported to have associations with mental health or down-regulation of inflammation or infection-related species. Moreover, correlation analysis revealed that the EG007-mediated altered microbiota had a significant correlation with the memory traits.

BackgroundOligometastatic disease (OMD) represents an indolent cancer status characterized by slow tumor growth and limited metastatic potential. The use of local therapy in the management of the condition continues to rise. This study aimed to investigate the advantage of pretreatment tumor growth rate in addition to baseline disease burden in characterizing OMDs, generally defined by the presence of ≤ 5 metastatic lesions.MethodsThe study included patients with metastatic melanoma treated with pembrolizumab. Gross tumor volume of all metastases was contoured on imaging before (TP-1) and at the initiation of pembrolizumab (TP0). Pretreatment tumor growth rate was calculated by an exponential ordinary differential equation model using the sum of tumor volumes at TP-1 and TP0 and the time interval between TP-1. and TP0. Patients were divided into interquartile groups based on pretreatment growth rate. Overall survival, progression-free survival, and subsequent progression-free survival were the study outcomes.ResultsAt baseline, median cumulative volume and number of metastases were 28.4 cc (range, 0.4-1194.8 cc) and 7 (range, 1-73), respectively. The median interval between TP-1 and TP0 was -90 days and pretreatment tumor growth rate (×10-2 days-1) was median 4.71 (range -0.62 to 44.1). The slow-paced group (pretreatment tumor growth rate ≤ 7.6 ×10-2 days-1, the upper quartile) had a significantly higher overall survival rate, progression-free survival, and subsequent progression-free survival compared to those of the fast-paced group (pretreatment tumor growth rate > 7.6 ×10-2 days-1). Notably, these differences were prominent in the subgroup with >5 metastases.ConclusionPretreatment tumor growth rate is a novel prognostic metric associated with overall survival, progression-free survival, and subsequent progression-free survival among metastatic melanoma patients, especially patients with >5 metastases. Future prospective studies should validate the advantage of disease growth rate plus disease burden in better defining OMDs.

Merremia umbellata Hallier f. (MU) has been used as an anti-inflammatory agent to treat burns and scales. However, the potential anti-inflammatory mechanisms of action of this plant have not been elucidated. This study aimed to assess the antioxidant and anti-inflammatory effects of the leaf and shoot of MU grown in Bangladesh. The MU extract exhibited antioxidant activities as demonstrated by DPPH and ABTS free-radical-scavenging activities and the total polyphenol and total flavonoid contents. MU extract significantly reduced the lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production in RAW264.7 macrophage. Accordingly, the gene levels of inducible NO synthase and cyclooxygenase-2 were suppressed. The MU extract alleviated the LPS-induced expression of TLR4, NF-κB, and inflammatory cytokines (TNF-α, IL-6, and IL-1β). The constituents of a MU extract were tentatively identified using UHPLC-PDA-QTOF/MS techniques. The main compounds were identified as 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, quercitrin, and 4,5-dicaffeoylquinic acid. Molecular docking analysis revealed that these compounds interact with TLR4 protein, with quercitrin showing the highest binding affinity among them. Overall, our findings demonstrate the antioxidant and in vitro anti-inflammatory activities of MU and its potential compounds to target the TLR4-NF-κB signaling pathway. These findings are potentially used to further explore promising natural food ingredients that are effective in regulating inflammation.

Pulmonary sclerosing pneumocytoma (PSP) is a tumor of pneumocytic origin that is classified as a benign neoplasm. To date, aggressive behavior of this tumor has rarely been reported. Here, we describe a case of a 56-year-old woman with a huge, 19-cm PSP that resulted in mediastinal shift and showed microscopic endobronchial invasion and necrosis. The differential diagnosis included malignant mesenchymal tumors, such as solitary fibrous tumor; however, PSP was confirmed based on the characteristic thyroid transcription factor 1 positivity and membranous expression of Ki-67 on immunohistochemical staining of tumor cells.

BackgroundMisperception of body weight is associated with various psychological and health problems, including obesity, eating disorders, and mental problems. To date, female-specific risk factors, including socioeconomic or health-related lifestyle features, or their indicative performance for the misperception in Asian women according to age groups remain unknown.ObjectivesTo investigate the prevalence and associated risk factors for the mismatch in self-perceived body weight and evaluated the classification performance of the identified risk factors across age groups in female adults.MethodsWe analyzed data of 22,121 women (age 19–97 years) from the 7-year Korea National Health and Nutrition Examination Survey dataset (2010-2016). We evaluated self-perceived body weight of the participants with their actual weight using the body mass index cut-off and grouped them by age: early adulthood (19–45), middle adulthood (46–59), and late adulthood (≥60). Logistic regression was conducted in each age group based on their weight misperception. The classification performance of the identified risk factors was evaluated with a bagging tree ensemble model with 5-fold cross-validation.Results22.2% (n=4,916) of the study participants incorrectly perceived their body weight, of which 14.1% (n=3,110) and 8.2% (n=1,806) were in the underestimated and overestimated groups. Among the age groups, the proportion of participants who misperceived their body weight was highest in late adulthood (31.8%) and the rate of overestimation was highest in early adulthood (14.1%). We found that a lower education level, absence of menopause, perception of themselves as unhealthy, and efforts for weight management were significantly associated with the overall misperception (overestimation or underestimation) of body weight across age groups. Based on the identified risk factors, the highest area under the receiver operating curve (AUROC) and accuracy of the best classification model (weight overestimation in all participants) were 0.758 and 0.761, respectively. Adding various associated lifestyle factors to the baseline model resulted in an average increase of 0.159 and 0.135 in AUROC for classifying weight underestimation and overestimation, respectively.ConclusionsAge, education level, marital status, absence of menopause, amount of exercise, efforts for weight management (gain, loss, and maintenance), and self-perceived health status were significantly associated with the mismatch of body weight.

Introduction: Time-restricted eating (TRE) has cardiometabolic health benefits by optimizing circadian rhythms. However, limited data are available on the effect of early TRE in young adults. The objective of this pre-post single-arm trial was to test the effect of TRE on body composition and cardiometabolic risk factors and to evaluate changes in meal and sleep timing by TRE among young adults with typically late bedtime. Methods: This 4-week intervention was conducted in healthy young adults aged 18-30 years. Dietary records with time logs were collected before and during the intervention and nutrient intake and meal timing were evaluated. Snack packages containing 20 g/day of protein were provided weekly. Body composition was measured weekly using bioelectrical impedance analysis. Blood samples were collected before and after the intervention, and cardiometabolic parameters were evaluated. Results: Of the 36 screened participants, 34 completed the study (completion rate 94.4%). The average age was 23.4 ± 2.9 years with 64.7% female. The mean wake-up time and bedtime were 09:16 ± 01:26 and 01:51 ± 01:39 with average sleep duration of 7.4 ± 1.4 hour. Body weight and fat mass, excluding muscle mass, were significantly reduced over 4 weeks compared to baseline only in the early TRE group starting before noon. The early TRE group also showed significantly reduced fasting glucose, fasting insulin, and serum triglyceride (TG) levels after 4 weeks. However, the late TRE group starting after noon showed no significant changes except a reduced TG level. The meal timing was changed by TRE, where the first meal was delayed and the last meal was shifted. Neither sleep duration nor timing was significantly changed by TRE. Energy intakes was not different, but protein intake increased from 19.2% to 22.6% due to snack packages during intervention. However, no significant correlation between nutrient intakes and body composition changes was found. There were no adverse events related to study participation. Conclusions: An early TRE regimen may be a feasible and effective strategy to manage body composition and cardiometabolic risk factors in young adults, without altering the sleep–wake cycle. Trial Registration: The Clinical Research Information Service (CRIS.nih.go.kr) identifier: KCT0006443

The prevalence of antimicrobial-resistant bacteria has become a major challenge worldwide. Methicillin-resistant Staphylococcus aureus (MRSA)—a leading cause of infections—forms biofilms on polymeric medical devices and implants, increasing their resistance to antibiotics. Antibiotic administration before biofilm formation is crucial. Raman spectroscopy was used to assess MRSA biofilm development on solid culture media from 0 to 48 h. Biofilm formation was monitored by measuring DNA/RNA-associated Raman peaks and protein/lipid-associated peaks. The search for an antimicrobial agent against MRSA biofilm revealed that Eugenol was a promising candidate as it showed significant potential for breaking down biofilm. Eugenol was applied at different times to test the optimal time for inhibiting MRSA biofilms, and the Raman spectrum showed that the first 5 h of biofilm formation was the most antibiotic-sensitive time. This study investigated the performance of Raman spectroscopy coupled with principal component analysis (PCA) to identify planktonic bacteria from biofilm conglomerates. Raman analysis, microscopic observation, and quantification of the biofilm growth curve indicated early adhesion from 5 to 10 h of the incubation time. Therefore, Raman spectroscopy can help in monitoring biofilm formation on a solid culture medium and performing rapid antibiofilm assessments with new antibiotics during the early stages of the procedure.

(1) Background and Objectives: There were two distinct coronavirus disease 2019 (COVID-19) outbreaks in 2020 and 2022 at a long-term mental health facility (LTMHF) in Gyeonggi Province, Korea. We aimed to compare the two outbreaks and identify differences in epidemiological and clinical outcomes due to changes in epidemic timing and management methods. (2) Materials and Methods: The structural, operational, and case-specific LTMHF data of COVID-19-confirmed patients during these outbreaks in 2020 and 2022 were retrospectively analyzed. (3) Results: Forty individuals (37 residents) in 2020 and thirty-nine (32 residents) in 2022 were confirmed to have COVID-19, and ten were infected twice. Facility isolation was implemented as an infection control measure, and one COVID-19-related death occurred in 2020. All residents and staff were vaccinated at least twice in 2022; moreover, in 2022, 38 patients (97.4%) received a third vaccination less than months before infection. The average Ct value of the cases in 2022 was significantly higher than that in 2020; however, vaccine-breakthrough (V-BT) and reinfection after vaccination rates were similar. (4) Conclusions: COVID-19 vaccination could help lower the viral load of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was inversely correlated with Ct values, and ventilation system improvements in health facilities might reduce transmissibility.

Abstract Background From patient-reported surveys and individual interviews by health care providers, we attempted to identify the significant factors related to the improvement of distress and fatigue for cancer survivors by text analysis with machine learning techniques, as the secondary analysis using the single institute data from the Korean Cancer Survivorship Center Pilot Project. Methods Surveys and in-depth interviews from 322 cancer survivors were analyzed to identify their needs and concerns. Among the keywords in the surveys, including EQ-VAS, distress, fatigue, pain, insomnia, anxiety, and depression, distress and fatigue were focused. The interview transcripts were analyzed via Korean-based text analysis with machine learning techniques, based on the keywords used in the survey. Words were generated as vectors and similarity scores were calculated by the distance related to the text’s keywords and frequency. The keywords and selected high-ranked ten words for each keyword based on the similarity were then taken to draw a network map. Results Most participants were otherwise healthy females younger than 50 years suffering breast cancer who completed treatment less than 6 months ago. As the 1-month follow-up survey’s results, the improved patients were 56.5 and 58.4% in distress and fatigue scores, respectively. For the improvement of distress, dyspepsia (p = 0.006) and initial scores of distress, fatigue, anxiety, and depression (p

Purpose: Various deformable image registration (DIR) methods have been used to evaluate organ deformations in 4-dimensional computed tomography (4D CT) images scanned during the respiratory motions of a patient. This study assesses the performance of 10 DIR algorithms using 4D CT images of 5 patients with fiducial markers (FMs) implanted during the postoperative radiosurgery of multiple lung metastases. Methods: To evaluate DIR algorithms, 4D CT images of 5 patients were used, and ground-truths of FMs and tumors were generated by physicians based on their medical expertise. The positions of FMs and tumors in each 4D CT phase image were determined using 10 DIR algorithms, and the deformed results were compared with ground-truth data. Results: The target registration errors (TREs) between the FM positions estimated by optical flow algorithms and the ground-truth ranged from 1.82 ± 1.05 to 1.98 ± 1.17 mm, which is within the uncertainty of the ground-truth position. Two algorithm groups, namely, optical flow and demons, were used to estimate tumor positions with TREs ranging from 1.29 ± 1.21 to 1.78 ± 1.75 mm. With respect to the deformed position for tumors, for the 2 DIR algorithm groups, the maximum differences of the deformed positions for gross tumor volume tracking were approximately 4.55 to 7.55 times higher than the mean differences. Errors caused by the aforementioned difference in the Hounsfield unit values were also observed. Conclusions: We quantitatively evaluated 10 DIR algorithms using 4D CT images of 5 patients and compared the results with ground-truth data. The optical flow algorithms showed reasonable FM-tracking results in patient 4D CT images. The iterative optical flow method delivered the best performance in this study. With respect to the tumor volume, the optical flow and demons algorithms delivered the best performance.

ABSTRACT Evidence for the concept of the “gut-brain axis” (GBA) has risen. Many types of research demonstrated the mechanism of the GBA and the effect of probiotic intake. Although many studies have been reported, most were focused on neurodegenerative disease and, it is still not clear what type of bacterial strains have positive effects. We designed an experiment to discover a strain that positively affects brain function, which can be recognized through changes in cognitive processes using healthy mice. The experimental group consisted of a control group and three probiotic consumption groups, namely, Lactobacillus acidophilus, Lacticaseibacillus paracasei, and Lacticaseibacillus rhamnosus. Three experimental groups fed probiotics showed an improved cognitive ability by cognitive-behavioral tests, and the group fed on L. acidophilus showed the highest score. To provide an understanding of the altered microbial composition effect on the brain, we performed full 16S-23S rRNA sequencing using Nanopore, and operational taxonomic units (OTUs) were identified at species level. In the group fed on L. acidophilus, the intestinal bacterial ratio of Firmicutes and Proteobacteria phyla increased, and the bacterial proportions of 16 species were significantly different from those of the control group. We estimated that the positive results on the cognitive behavioral tests were due to the increased proportion of the L. acidophilus EG004 strain in the subjects’ intestines since the strain can produce butyrate and therefore modulate neurotransmitters and neurotrophic factors. We expect that this strain expands the industrial field of L. acidophilus and helps understand the mechanism of the gut-brain axis. IMPORTANCE Recently, the concept of the “gut-brain axis” has risen and suggested that microbes in the GI tract affect the brain by modulating signal molecules. Although many pieces of research were reported in a short period, a signaling mechanism and the effects of a specific bacterial strain are still unclear. Besides, since most of the research was focused on neurodegenerative disease, the study with a healthy animal model is still insufficient. In this study, we show using a healthy animal model that a bacterial strain (Lactobacillus acidophilus EG004) has a positive effect on mouse cognitive ability. We experimentally verified an improved cognitive ability by cognitive behavioral tests. We performed full 16S-23S rRNA sequencing using a Nanopore MinION instrument and provided the gut microbiome composition at the species level. This microbiome composition consisted of candidate microbial groups as a biomarker that shows positive effects on cognitive ability. Therefore, our study suggests a new perspective for probiotic strain use applicable for various industrialization processes.

The orphan nuclear receptor, estrogen-related receptor γ (ERRγ) is a constitutively active transcription factor involved in mitochondrial metabolism and energy homeostasis. GSK5182, a specific inverse agonist of ERRγ that inhibits transcriptional activity, induces a conformational change in ERRγ, resulting in a loss of coactivator binding. However, the molecular mechanism underlying the stabilization of the ERRγ protein by its inverse agonist remains largely unknown. In this study, we found that GSK5182 inhibited ubiquitination of ERRγ, thereby stabilizing the ERRγ protein, using cell-based assays and confocal image analysis. Y326 of ERRγ was essential for stabilization by GSK5182, as ligand-induced stabilization of ERRγ was not observed with the ERRγ-Y326A mutant. GSK5182 suppressed ubiquitination of ERRγ by the E3 ligase Parkin and subsequent degradation. The inhibitory activity of GSK5182 was strong even when the ERRγ protein level was elevated, as ERRγ bound to GSK5182 recruited a corepressor, small heterodimer partner-interacting leucine zipper (SMILE), through the activation function 2 (AF-2) domain, without alteration of the nuclear localization or DNA-binding ability of ERRγ. In addition, the AF-2 domain of ERRγ was critical for the regulation of protein stability. Mutants in the AF-2 domain were present at higher levels than the wild type in the absence of GSK5182. Furthermore, the ERRγ-L449A/L451A mutant was no longer susceptible to GSK5182. Thus, the AF-2 domain of ERRγ is responsible for the regulation of transcriptional activity and protein stability by GSK5182. These findings suggest that GSK5182 regulates ERRγ by a unique molecular mechanism, increasing the inactive form of ERRγ via inhibition of ubiquitination.

Abstract Chondroradionecrosis (CRN) is an infrequent phenomenon after definitive RT. The clinical manifestation is usually difficult to distinguish from that of tumor recurrence; however, clinicians should be aware of the possibility of CRN.

The occurrence of low-frequency instability (LFI) appears to be related to multiple interactions among many complex physical processes, such as vortex shedding, boundary-layer oscillation, and additional combustion in the post-combustion chamber. In this study, two combustion tests were conducted to suppress LFI and to examine which physical processes its occurrence was most sensitive. In the first test, two fuel inserts were used to modify the formation of a boundary layer, vortex shedding at the end of the fuel, and vortex impingement. In the second test, the fuel insert located at the front end was replaced with swirl injection. The first test was aimed at controlling and suppressing the initiation of LFI using fuel inserts, through which a small step appeared gradually due to differences in the regression rates of the two materials, i.e., polymethyl methacrylate and high-density polyethylene. The test results confirmed that (i) there are physical connections among several processes, such as the thermoacoustic coupling between p′and q′ and the oscillations of the upstream boundary flow, and (ii) LFI suppression is possible by disrupting or eliminating the connections among these physical processes. The second test was also aimed to control LFI while minimizing the deviation in combustion performance using proper swirl injection along with a fuel insert. Even when replaced by swirl injection, LFI suppression was still possible and showed reasonable combustion performance without causing too much deviation from the baseline in terms of the oxygen-to-fuel ratio and the fuel regression rate.

DN203368 ((E)-3-[1-(4-[4-isopropylpiperazine-1-yl]phenyl) 3-methyl-2-phenylbut-1-en-1-yl] phenol) is a 4-hydroxy tamoxifen analog that is a dual inverse agonist of estrogen-related receptor β/γ (ERRβ/γ). ERRγ is an orphan nuclear receptor that plays an important role in development and homeostasis and holds potential as a novel therapeutic target in metabolic diseases such as diabetes mellitus, obesity, and cancer. ERRβ is also one of the orphan nuclear receptors critical for many biological processes, such as development. We investigated the in vitro metabolism of DN203368 by conventional and metabolomic approaches using high-resolution mass spectrometry. The compound (100 μM) was incubated with rat and human liver microsomes in the presence of NADPH. In the metabolomic approach, the m/z value and retention time information obtained from the sample and heat-inactivated control group were statistically evaluated using principal component analysis and orthogonal partial least-squares discriminant analysis. Significant features responsible for group separation were then identified using tandem mass spectra. Seven metabolites of DN203368 were identified in rat liver microsomes and the metabolic pathways include hydroxylation (M1-3), N-oxidation (M4), N-deisopropylation (M5), N,N-dealkylation (M6), and oxidation and dehydrogenation (M7). Only five metabolites (M2, M3, and M5-M7) were detected in human liver microsomes. In the conventional approach using extracted ion monitoring for values of mass increase or decrease by known metabolic reactions, only five metabolites (M1-M5) were found in rat liver microsomes, whereas three metabolites (M2, M3, and M5) were found in human liver microsomes. This study revealed that nontargeted metabolomics combined with high-resolution mass spectrometry and multivariate analysis could be a more efficient tool for drug metabolite identification than the conventional approach. These results might also be useful for understanding the pharmacokinetics and metabolism of DN203368 in animals and humans.

Acne is a chronic inflammatory skin disease induced by Cutibacterium acnes. Recently, the effects of probiotics, prebiotics and synbiotics have been researched for the treatment of skin diseases in humans. However, the synbiotic effect of probiotics and prebiotic Curcuma longa rhizome extract (CLE) on C. acnes remains ambiguous. Therefore, the aim of this study was to investigate the synergistic antibacterial activities of probiotic lactic acid bacteria (LAB) with CLE as a synbiotic against C. acnes. Agar well diffusion assays were performed to determine the inhibitory effects of each combination of one of five Lactobacillus sp. with CLE as synbiotics against C. acnes KCTC 3314. Among them, the comparison between the average diameters of inhibition zones showed that the synbiotic combination of Lactobacillus acidophilus A001F8 and CLE significantly increased the inhibition zone diameters against C. acnes, compared to the use of Lactobacillus acidophilus A001F8 or CLE alone (p < 0.05). In conclusion, the synbiotics of probiotic LAB and CLE showed synergistic antibacterial effects against C. acnes, suggesting therapeutic potential for this synbiotic combination in the development of cosmetics or medicine against C. acnes.

Bone morphogenetic protein 6 (BMP6) is a multifunctional growth factor involved in organ development and homeostasis. BMP6 controls expression of the liver hormone, hepcidin, and thereby plays a crucial role in regulating iron homeostasis. BMP6 gene transcriptional regulation in liver is largely unknown, but would be of great help to externally modulate iron load in pathologic conditions. Here, we describe a detailed molecular mechanism of hepatic BMP6 gene expression by an orphan nuclear receptor, estrogen-related receptor γ (ERRγ), in response to the pro-inflammatory cytokine interleukin 6 (IL-6). Recombinant IL-6 treatment increases hepatic ERRγ and BMP6 expression. Overexpression of ERRγ is sufficient to increase BMP6 gene expression in hepatocytes, suggesting that IL-6 is upstream of ERRγ. In line, knock-down of ERRγ in cell lines or a hepatocyte specific knock-out of ERRγ in mice significantly decreases IL-6 mediated BMP6 expression. Promoter studies show that ERRγ directly binds to the ERR response element (ERRE) in the mouse BMP6 gene promoter and positively regulates BMP6 gene transcription in IL-6 treatment conditions, which is further confirmed by ERRE mutated mBMP6-luciferase reporter assays. Finally, an inverse agonist of ERRγ, GSK5182, markedly inhibits IL-6 induced hepatic BMP6 expression in vitro and in vivo. Taken together, these results reveal a novel molecular mechanism on ERRγ mediated transcriptional regulation of hepatic BMP6 gene expression in response to IL-6.

BACKGROUND:Smokers tend to weigh less than never smokers, while successful quitting leads to an increase in body weight. Because smokers and non-smokers may differ in genetic and environmental family background, we analysed data from twin pairs in which the co-twins differed by their smoking behaviour to evaluate if the association between smoking and body mass index (BMI) remains after controlling for family background. METHODS AND FINDINGS:The international CODATwins database includes information on smoking and BMI measured between 1960 and 2012 from 156,593 twin individuals 18-69 years of age. Individual-based data (230,378 measurements) and data of smoking discordant twin pairs (altogether 30,014 pairwise measurements, 36% from monozygotic [MZ] pairs) were analysed with linear fixed-effects regression models by 10-year periods. In MZ pairs, the smoking co-twin had, on average, 0.57 kg/m2 lower BMI in men (95% confidence interval (CI): 0.49, 0.70) and 0.65 kg/m2 lower BMI in women (95% CI: 0.52, 0.79) than the never smoking co-twin. Former smokers had 0.70 kg/m2 higher BMI among men (95% CI: 0.63, 0.78) and 0.62 kg/m2 higher BMI among women (95% CI: 0.51, 0.73) than their currently smoking MZ co-twins. Little difference in BMI was observed when comparing former smoking co-twins with their never smoking MZ co-twins (0.13 kg/m2, 95% CI 0.04, 0.23 among men; -0.04 kg/m2, 95% CI -0.16, 0.09 among women). The associations were similar within dizygotic pairs and when analysing twins as individuals. The observed series of cross-sectional associations were independent of sex, age, and measurement decade. CONCLUSIONS:Smoking is associated with lower BMI and smoking cessation with higher BMI. However, the net effect of smoking and subsequent cessation on weight development appears to be minimal, i.e. never more than an average of 0.7 kg/m2.

Hair loss is a major dermatological disease in veterinary and human medicine. Active studies on hair regeneration with mesenchymal stem cells have been performed in an effort to solve the limitations of conservative treatments in human medicine. Our understanding of the canine hair follicle (HF), considering a useful model for the study of the human alopecia, is limited. This study was designed to broaden our understanding of canine dermal papilla (DP), and to reconstruct dermal papilla-like tissue (DPLT) using canine adipose-derived mesenchymal stem cells (AD-MSCs), as an alternative to actual DP. We cultured canine DPs, observed their culture patterns and compared their expression level of DP-related genes and proteins with those of DPLTs by performing RT-PCR analysis and Western blotting. Canine dermal papilla cells (DPCs) showed multilayer culture patterns with pseudo-papillae. Reconstruction of DPLTs was performed successfully. Not only were they morphologically similar to actual DPs, but we also observed similarities between DPCs and DPLTs in molecular characteristics. These findings suggested that DPLT was a viable substitute for DP. This study will not only be helpful for understanding the morphological and molecular characteristics of canine DPCs, but may also serve as a basis for understanding human hair follicle biology and potential therapeutic strategies for alopecia.

Molecular characterization technology in genetically modified organisms, in addition to how transgenic biotechnologies are developed now require full transparency to assess the risk to living modified and non-modified organisms. Next generation sequencing (NGS) methodology is suggested as an effective means in genome characterization and detection of transgenic insertion locations. In the present study, we applied NGS to insert transgenic loci, specifically the epidermal growth factor (EGF) in genetically modified rice cells. A total of 29.3 Gb (~72× coverage) was sequenced with a 2 × 150 bp paired end method by Illumina HiSeq2500, which was consecutively mapped to the rice genome and T-vector sequence. The compatible pairs of reads were successfully mapped to 10 loci on the rice chromosome and vector sequences were validated to the insertion location by polymerase chain reaction (PCR) amplification. The EGF transgenic site was confirmed only on chromosome 4 by PCR. Results of this study demonstrated the success of NGS data to characterize the rice genome. Bioinformatics analyses must be developed in association with NGS data to identify highly accurate transgenic sites.

Fibrinogen, 1 of 13 coagulation factors responsible for normal blood clotting, is synthesized by hepatocytes. Detailed roles of the orphan nuclear receptors regulating fibrinogen gene expression have not yet been fully elucidated. Here, we identified estrogen-related receptor gamma (ERRγ) as a novel transcriptional regulator of human fibrinogen gene expression. Overexpression of ERRγ specially increased fibrinogen expression in human hepatoma cell line. Cannabinoid receptor types 1(CB1R) agonist arachidonyl-2'-chloroethylamide (ACEA) up-regulated transcription of fibrinogen via induction of ERRγ, whereas knockdown of ERRγ attenuated fibrinogen expression. Deletion analyses of the fibrinogen γ (FGG) gene promoter and ChIP assays revealed binding sites of ERRγ on human fibrinogen γ gene promoter. Moreover, overexpression of ERRγ was sufficient to increase fibrinogen gene expression, whereas treatment with GSK5182, a selective inverse agonist of ERRγ led to its attenuation in cell culture. Finally, fibrinogen and ERRγ gene expression were elevated in liver tissue of obese patients suggesting a conservation of this mechanism. Overall, this study elucidates a molecular mechanism linking CB1R signaling, ERRγ expression and fibrinogen gene transcription. GSK5182 may have therapeutic potential to treat hyperfibrinogenemia.

Aminoacyl-tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1)-derived peptide (AdP) has been developed as a cosmeceutical ingredient for skin anti-aging given its fibroblast-activating (FA) and melanocyte-inhibiting (MI) functions. However, a suitable strategy for the topical delivery of AdP was required due to its low-permeable properties. In this study, FA and MI domains of AdP (FA-AdP and MI-AdP, respectively) were determined by functional domain mapping, where the activities of several fragments of AdP on fibroblast and melanocyte were tested, and a hydrosol-based topical delivery system for these AdP fragments was prepared. The excipient composition of the hydrosol was optimized to maximize the viscosity and drying rate by using Box-Behnken design. The artificial skin deposition of FA-AdP-loaded hydrosol was evaluated using Keshary-Chien diffusion cells equipped with Strat-M membrane (STM). The quantification of the fluorescent dye-tagged FA-AdP in STM was carried out by near-infrared fluorescence imaging. The optimized hydrosol showed 127-fold higher peptide deposition in STM than free FA-AdP (p < 0.05). This work suggests that FA- and MI-AdP are active-domains for anti-wrinkle and whitening activities, respectively, and the hydrosol could be used as a promising cosmetic formulation for the delivery of AdPs to the skin.

Root hairs are tubular outgrowths that originate from epidermal cells. Exposure of Arabidopsis to cadmium (Cd) and arsenic [arsenite, As(III)] increases root hair density and length. To examine the underlying mechanism, we measured the expression of genes involved in fate determination and morphogenesis of root hairs. Cd and As(III) downregulated TTG1 and GL2 (negative regulators of fate determination) and upregulated GEM (positive regulator), suggesting that root hair fate determination is stimulated by Cd and As(III). Cd and As(III) increased the transcript levels of genes involved in root hair initiation (RHD6 and AXR2) and root hair elongation (AUX1, AXR1, ETR1, and EIN2) except CTR1. DR5::GUS transgenic Arabidopsis showed a higher DR5 expression in the root tip, suggesting that Cd and As(III) increased the auxin content in the root tip. Knockdown of TTG1 in Arabidopsis resulted in increased root hair density and decreased root hair length compared with the control (Col-0) on 1/2 MS media. This phenotype may be attributed to the downregulation of GL2 and CTR1 and upregulation of RHD6. By contrast, gem mutant plants displayed a decrease in root hair density and length with reduced expression of RHD6, AXR2, AUX1, AXR1, ETR1, CTR1, and EIN2. Taken together, our results indicate that fate determination, initiation, and elongation of root hairs are stimulated in response to Cd and As(III) through the modulation of the expression of genes involved in these processes in Arabidopsis.

Fibroblast growth factor 21 (FGF21), a stress inducible hepatokine, is synthesized in the liver and plays important roles in glucose and lipid metabolism. However, the mechanism of hepatic cannabinoid type 1 (CB1) receptor-mediated induction of FGF21 gene expression is largely unknown.Activation of the hepatic CB1 receptor by arachidonyl-2'-chloroethylamide (ACEA), a CB1 receptor selective agonist, significantly increased FGF21 gene expression. Overexpression of estrogen-related receptor (ERR) γ increased FGF21 gene expression and secretion both in hepatocytes and mice, whereas knockdown of ERRγ decreased ACEA-mediated FGF21 gene expression and secretion. Moreover, ERRγ, but not ERRα and ERRβ, induced FGF21 gene promoter activity. In addition, deletion and mutation analysis of the FGF21 promoter identified a putative ERRγ-binding motif (AGGTGC, a near-consensus response element). A chromatin immunoprecipitation assay revealed direct binding of ERRγ to the FGF21 gene promoter. Finally, GSK5182, an ERRγ inverse agonist, significantly inhibited hepatic CB1 receptor-mediated FGF21 gene expression and secretion.Based on our data, we conclude that ERRγ plays a key role in hepatic CB1 receptor-mediated induction of FGF21 gene expression and secretion.

This paper considers Indra Sinha's Animal's People (2007), a fictional re-telling of the Union Carbide Bhopal disaster, as a productive site of mutual engagement between postcolonial studies and disability studies, two fields rarely in dialogue. Dominant models of disability, I argue, do not translate to formerly colonial sites and/or sites that bear the burden of global capitalism. The uneven processes of globalization—which produce disabling environments—necessitate that we revise established conceptions of disability, which are derived largely from US/UK contexts. I explore a socio-spatial model that emphasizes the necessity of specific locational axes in figurations of disability. This enables more flexible understandings of embodiment, which may shift and be shifted by the particularities of space. A victim of the disaster, Animal--the novel's protagonist--navigates Bhopal’s streets on all fours. His unique spatial imaginary, contingent on his particular form of embodiment, produces a local and embodied knowledge that foregrounds points of convergence between anti-colonial, anti-capitalist, and disability politics. Keywords: postcolonialism, globalization, Bhopal India, Union Carbide, neoliberalism, transnational, contemporary English literature, industrial disaster, environmental studies

GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.