Stromal Rigidity Stress Accelerates Pancreatic Intraepithelial Neoplasia Progression and Chromosomal Instability via Nuclear Protein Tyrosine Kinase 2 Localization.

Because the mechanotransduction by stromal stiffness stimulates the rupture and repair of the nuclear envelope in pancreatic progenitor cells, accumulated genomic aberrations are under selection in the tumor microenvironment. Analysis of cell growth, micronuclei, and phosphorylated Ser-139 residue of the histone variant H2AX (γH2AX) foci linked to mechanotransduction pressure in vivo during serial orthotopic passages of mouse KrasLSL-G12D/+;Trp53flox/flox;Pdx1-Cre (KPC) cancer cells in the tumor and in migrating through the size-restricted 3-µm micropores. To search for pancreatic cancer cell-of-origin, analysis of single-cell data sets revealed that the extracellular matrix shaped an alternate route of acinar-ductal transdifferentiation of acinar cells into topoisomerase II α (TOP2A)-overexpressing cancer cells and derived subclusters with copy number amplifications in MYC-PTK2 (protein tyrosine kinase 2) locus and PIK3CA. High-PTK2 expression is associated with 171 differentially methylated CpG loci, 319 differentially expressed genes, and poor overall survival in The Cancer Genome Atlas-Pancreatic Adenocarcinoma cohort. Abolished RGD-integrin signaling by disintegrin KG blocked the PTK2 phosphorylation, increased cancer apoptosis, decreased vav guanine nucleotide exchange factor 1 (VAV1) expression, and prolonged overall survival in the KPC mice. Reduction of α-smooth muscle actin deposition in the CD248 knockout KPC mice remodeled the tissue stroma and down-regulated TOP2A expression in the epithelium. In summary, stromal stiffness induced the onset of cancer cells-of-origin by ectopic TOP2A expression, and the genomic amplification of MYC-PTK2 locus via alternative transdifferentiation of pancreatic progenitor cells is the vulnerability useful for disintegrin KG treatment.

Organocatalytic enantioselective Mannich and retro-Mannich reactions and combinations of these reactions to afford tetrasubstituted α-amino acid derivatives.

Organocatalytic asymmetric Mannich reactions and kinetic resolutions of the products via retro-Mannich reactions that afford enantiomerically enriched tetrasubstituted α-amino acid derivatives (α,α-disubstituted-α-amino acid derivatives) were developed. Furthermore, the combination of the Mannich reaction and the retro-Mannich reaction allowed access to products with almost perfect enantiopurities.

Different autism measures targeting different severity levels in children with autism spectrum disorder.

The Childhood Autism Rating Scale™, Second Edition (CARS™-2) and Social Responsiveness Scale™, Second Edition (SRS™-2) are two measures for identifying autism symptoms. The CARS™-2 has two versions: Standard (CARS-ST) and High-Functioning (CARS-HF). To better understand their properties, this study aimed to investigate: (1) the associations among the CARS-ST, CARS-HF and the SRS™-2, and (2) the severity consistency between the CARS-ST and the CARS-HF. A sample of 125 children with autism spectrum disorder was recruited (mean age: 80.98 months, SD = 16.08). Based on Verbal Comprehension Index (VCI), children were divided into two groups: low severity level of autism spectrum disorder (LSL-ASD: VCI ≥ 80) and high severity level of autism spectrum disorder (HSL-ASD: VCI < 80). All children were evaluated with the CARS-ST and the SRS™-2, and the HF group, with the CARS-HF as well. In the LSL group, the CARS-ST and the CARS-HF had high correlation (r = 0.852, p < .001). Both versions had small to moderate correlations with the SRS™-2 (r = 0.130-0.491). In the HSL group, no significant correlations were found between the CARS-ST and SRS™-2 (p > .05). The CARS-HF and the CARS-ST had low severity consistency (Kappa = 0.376, p < .01). The CARS-ST and the CARS-HF had high correlations but low severity consistency. Different correlation patterns were found between the CARS™-2 and the SRS™-2 in the LSL and HSL groups. The results should help clinicians better understand the properties of the measures and choose appropriate measures when assessing autism symptoms.

Enhancing Taiwan's healthcare sustainability: A Delphi study on national medicines policy reforms.

BACKGROUND/PURPOSE: The National Medicines Policy (NMP) is crucial as it sets the framework for ensuring access to affordable, high-quality medicines and promoting their rational use, which is essential for public health and the efficiency of the healthcare system. This study aims to evaluate the current state of Taiwan's NMP, identify pressing issues for improvement, and establish actionable suggestions through expert consensus to ensure the sustainable provision and use of medications. METHODS: A modified two-round Delphi technique was employed. The first-round survey identified key issues and suggestions for policy improvement, while the second-round survey evaluated the feasibility and effectiveness of these suggestions. The expert panel, consisting of 50 specialists from pharmacy, medicine, public health, and the pharmaceutical industry, evaluated key issues related to the NMP's efficacy using a 4-point Likert scale. RESULTS: The first-round survey identified 13 key issues in Taiwan's NMP, primarily focusing on the rational use and accessibility of medications. The second-round survey proposed 54 policy improvement suggestions for these issues, of which 20 were considered strong suggestions and 23 were moderate suggestions. The policy recommendations cover medication reimbursement, pharmacy professional services, administration, legislation, and education. CONCLUSION: The study highlights the urgent need for reforms in Taiwan's NMP, providing specific policy improvement suggestions to ensure high-quality medications and pharmaceutical services while supporting the sustainable operation of Taiwan's NHI system. The study underscores the significance of proactive measures to fortify healthcare sustainability in the face of evolving healthcare landscapes.

Impact of an integrated medication management model on the collaborative working relationship among healthcare professionals in a hospital: an explanatory mixed methods study.

An integrated medication management (IMM) model was implemented in a medical center ward to improve the delivery of clinical pharmaceutical services (CPSs). This model incorporated a ward-based clinical pharmacist who performed medication reconciliation and medication reviews. It was perceived to promote interprofessional collaboration between pharmacists and non-pharmacist healthcare professionals (NPHPs, including attending physicians, nurse practitioners, and registered nurses). This study aimed to evaluate the effects of the IMM on NPHPs' intentions to collaborate with pharmacists and understand the mechanism of the impact of the IMM on interprofessional collaboration. A sequential explanatory mixed methods design was employed in the study. Initially, a questionnaire was administered to assess the effects of the IMM on NPHPs' intentions to collaborate with pharmacists. The NPHPs' experiences with the IMM were then documented using semi-structured interviews with inductive thematic analysis. Fifty-eight NPHPs completed the questionnaire, and NPHPs from the intervention ward reported a higher intention to discuss patient-related medication issues with pharmacists, indicating collaboration. Eleven NPHPs were interviewed, and they stated having better working relationships with pharmacists, experiencing more effective CPSs, and noting improved communication with pharmacists. The integration of quantitative and qualitative findings demonstrates that the critical mechanism of the IMM in promoting collaborative relationships is to integrate pharmacists into medical practice, which familiarizes NPHPs with pharmacists' roles, improves communication, and enables pharmacists to identify NPHPs' needs. To summarize, allowing ward-based pharmacists to engage in medical teams on a regular basis appears vital for improving interprofessional teamwork. Furthermore, stakeholders aiming to promote CPS in their institutions should consider the needs and communication channels among NPHPs.

The animated assessment of theory of mind for people with schizophrenia (AToMS): development and psychometric evaluation.

Theory of mind (ToM) deficits in people with schizophrenia have been reported and associated with impaired social interactions. Thus, ToM deficits may negatively impact social functioning and warrant consideration in treatment development. However, extant ToM measures may place excessive cognitive demands on people with schizophrenia. Therefore, the study aimed to develop a comprehensible Assessment of ToM for people with Schizophrenia (AToMS) and evaluate its psychometric properties. The AToMs was developed in 5 stages, including item formation, expert review, content validity evaluation, animation production, and cognitive interviews of 25 people with schizophrenia. The psychometric properties of the 16-item AToMS (including reliability and validity) were then tested on 59 people with schizophrenia. The newly developed animated AToMS assesses 8 ToM concepts in the cognitive and affective dimensions while placing minimal neurocognitive demands on people with schizophrenia. The AToMS presented satisfactory psychometric properties, with adequate content validity (content validity index = 0.91); mostly moderate item difficulty (item difficulty index = 0.339-0.966); good discrimination (coefficients = 0.379-0.786), internal consistency (Cronbach's α = 0.850), and reliability (intraclass correlation coefficient = 0.901 for test-retest, 0.997 for inter-rater); and satisfactory convergent and divergent validity. The AToMS is reliable and valid for evaluating ToM characteristics in people with schizophrenia. Future studies are warranted to examine the AToMS in other populations (e.g., people with affective disorders) to cross-validate and extend its utility and psychometric evidence.

Using Artificial Intelligence to Identify the Associations of Children's Performance of Coloring, Origami, and Copying Activities With Visual-Motor Integration.

IMPORTANCE: Performance of coloring, origami, and copying activities reflects children's visual-motor integration (VMI), but the levels of association remain unclear. OBJECTIVE: To use artificial intelligence (AI) to investigate associations of performance of coloring, origami, and copying activities with VMI. DESIGN: Cross-sectional study. SETTING: Kindergartens. PARTICIPANTS: A sample of 370 children (182 boys and 188 girls) in the second and third years of kindergarten. OUTCOMES AND MEASURES: Beery-Buktenica Developmental Test of Visual-Motor Integration, 6th Edition (VMI-6). RESULTS: Data for preschool children from an ongoing project were retrieved. AI models were trained to use photographs of activity products to predict total score on the VMI-6. R2 values were used to identify the variance in VMI-6 standardized scores explained by predicted scores from the activities. That is, R2 values reflected associations between activity performance and VMI. The R2 values for the combination of origami and copying were the largest (.390-.577). These R2 values were larger than those for each individual activity (.340-.473) and similar to those for the combination of all three activities (.400-.550). CONCLUSIONS AND RELEVANCE: Because moderate R2 values were found between performance of the three activity products and VMI, the three activities have high potential for use in identifying children's level of VMI or as teaching materials to facilitate the development of children's VMI. Furthermore, combining origami and copying activities is recommended for teachers and clinicians who need to address VMI. What This Article Adds: A combination of origami and copying activities had the strongest associations with children's VMI. Teachers and clinicians can use these two activities when addressing VMI development among preschool children.

The Biosynthetic Gene Cluster of Mushroom-Derived Antrocin Encodes Two Dual-Functional Haloacid Dehalogenase-like Terpene Cyclases.

(-)-Antrocin (1), produced by the medicinal mushroom Antrodia cinnamomea, is a potent antiproliferative compound. The biosynthetic gene cluster of 1 was identified, and the pathway was characterized by heterologous expression. We characterized a haloacid dehalogenase-like terpene cyclase AncC that biosynthesizes the drimane-type sesquiterpene (+)-albicanol (2) from farnesyl pyrophosphate (FPP). Biochemical characterization of AncC, including kinetic studies and mutagenesis, demonstrated the functions of two domains: a terpene cyclase (TC) and a pyrophosphatase (PPase). The TC domain first cyclizes FPP to albicanyl pyrophosphate, and the PPase domain then removes the pyrophosphate to form 2. Intriguingly, AncA (94 % sequence identity to AncC), in the same gene cluster, converts FPP into (R)-trans-γ-monocyclofarnesol instead of 2. Notably, Y283/F375 in the TC domain of AncA serve as a gatekeeper in controlling the formation of a cyclofarnesoid rather than a drimane-type scaffold.

High levels of screen time were associated with increased probabilities of lagged development in 3-year-old children.

AIM: This study determined whether higher screen time was associated with the development of 3-year-old children in Taiwan. It also examined whether differences would be found between television and other screen-based media in the probability of lagged development. METHODS: We examined 2139 children aged 3 years and their parents. The association between daily screen time was assessed using multiple logistic regression analysis. All the odds ratios (ORs) were calculated using the rates of lagged developmental achievement, with the group who used screens for less than 1 h a day as the reference category. Screen time comprised television and other screen-based media, such as smartphones, touch screens, computers and laptops. RESULTS: Children who used screens for more than 3 h per day had the lowest developmental scores and highest probabilities of lagged development. The children who used other screen-based media for more than 1 h per day had greater probabilities of lagged developmental achievements (ORs 1.85-4.98, all p < 0.05) than those who watched television for the same amount of time (OR 1.41-2.77, all p < 0.05). CONCLUSION: Increased screen time was associated with higher probabilities of lagged developmental achievement in multiple development domains in 3-year-old children, particularly other screen-based media.

Impact of integrated medication management program on medication errors in a medical center: an interrupted time series study.

BACKGROUND: Medication errors (MEs) are harmful to patients during hospitalization, especially elderly patients. To reduce MEs, an integrated medication management (IMM) model was developed in a 2500-bed medical center, allowing a clinical pharmacist to participate in the daily ward round and perform medication reconciliation and medication reviews. This study aimed to evaluate the impact of the IMM model on MEs and medication utilization using a quasi-experimental design. METHODS: We conducted an interrupted time-series study using the aggregated data of monthly admissions from two wards of a medical center, where one ward served as the intervention and the other served as the external control. The pre- and post-intervention phases comprised of 40 and 12 monthly observational units, respectively. The primary outcome was the mean number of ME reports, which were further investigated for different ME types. The mean number of daily inpatient prescriptions, mean number of daily self-prepared medications, and median daily medication costs were measured. All outcomes were measured per admission episode. Segmented regression was used to evaluate the level and slope changes in the outcomes after IMM model implementation, and subgroup analyses were performed to examine the effects on different groups. RESULTS: After IMM model implementation, the mean number of ME reports increased (level change: 1.02, 95% confidence interval [CI]: 0.68 to 1.35, P < 0.001). The number of reports has shown a dramatic increase in omissions or medication discrepancies, inappropriate drug choices, and inappropriate routes or formulations. Furthermore, the mean number of daily inpatient prescriptions was reduced for patients aged ≥75 years (level change: -1.78, 95% CI: -3.06 to -0.50, P = 0.009). No significant level or slope change was observed in the control ward during the post-intervention phase. CONCLUSIONS: The IMM model improved patient safety and optimized medication utilization by increasing the reporting of MEs and decreasing the number of medications used.

Cognitive Predictors of Social Interaction in Daily Contexts Among Children With Autism Spectrum Disorder.

IMPORTANCE: Theory of mind (ToM) and executive function (EF) are often used to explain social interaction deficits in children with autism spectrum disorder (ASD), but no behavioral studies have specifically examined their relationship. OBJECTIVE: To investigate the cognitive correlates of social interaction in daily contexts by ToM as well as cool and hot EFs among children with ASD. DESIGN: Cross-sectional study. SETTING: Teaching hospitals, clinics, and developmental centers. PARTICIPANTS: One hundred thirty-two children with ASD and their caregivers. OUTCOMES AND MEASURES: Measurements included the Vineland Adaptive Behavior Scales, Theory of Mind Task Battery, Dimensional Change Card Sort, and Children's Gambling Task, respectively, for children's daily social interaction, ToM, cool EF, and hot EF. Pearson's correlation analyses and three hierarchical regression models were conducted to identify the significant predictors of daily social interaction while controlling for verbal comprehension, measured using the Verbal Comprehension Index (VCI) of two Wechsler scales. RESULTS: ToM and cool EF were significant cognitive predictors of social interaction in daily contexts in children with ASD whose verbal comprehension was average or above average. CONCLUSIONS AND RELEVANCE: Our results suggest that ToM and cool EF are predictors of social interaction in daily contexts when considering children's verbal comprehension. Hot EF was not a significant predictor, contrary to our hypothesis. This behavioral study fills a research gap by enhancing the understanding of important cognitive correlates of social interaction in daily contexts for children with ASD to improve evaluation and intervention planning with this population. What This Article Adds: This study identified two cognitive predictors, ToM and cool EF, of social interaction in daily contexts for children with ASD. In addition to verbal comprehension, occupational therapy practitioners should assess ToM and cool EF to inform more comprehensive evaluation and intervention planning to improve social interaction in daily contexts for children with ASD.

Development of the Computerized Adaptive Test of Motor Development (MD-CAT) Adopting Multidimensional Rasch Analysis.

OBJECTIVE: This study aimed to develop the Computerized Adaptive Test of Motor Development (MD-CAT) in preschool children based on multidimensional Rasch analysis. DESIGN: A retrospective study with cross-sectional design. SETTING: A medical center. PARTICIPANTS: A total of 1738 children (N=1738). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: MD-CAT. RESULTS: Multidimensional Rasch analysis was used to develop the item bank of the MD-CAT. The item bank of the MD-CAT contained 74 items, with 44 and 30 items, respectively, for the subscales of gross and fine motor skills. High correlation existed between the 2 subscales (r=0.96). Three stopping rules were set for the MD-CAT: (1) the person reliability achieved 0.95 or the limited reliability increase by <0.01; (2) at least 3 items were assessed in each dimension; and (3) the number of items used for assessment reached 16. Based on the 3 stopping rules, the MD-CAT had high correlations with its total test length (r=0.87-0.98 for the 2 dimensions), indicating sufficient construct validity. The MD-CAT also had adequate diagnostic validity (area under the curve=0.72-0.93) and efficiency (an average of 3-6 items used for the assessment). CONCLUSIONS: The MD-CAT has high precision and efficiency, good construct validity, and high diagnostic validity. The results of our study indicate that the MD-CAT can be useful in clinical practice and in research as a diagnostic measure.

Conversation-Based Information Delivery Method for Facility Management.

Facility management platforms are widely used in the facility maintenance phase of the building life cycle. However, a large amount of complex building information affects facility managers' efficiency and user experience in retrieving specific information on the facility management platform. Therefore, this research aims to develop a conversation-based method to improve the efficiency and user experience of facility management information delivery. The proposed method contains four major modules: decision mechanism, equipment dataset, intent analysis, and knowledge base. A chatbot prototype was developed based on the proposed method. The prototype was then validated through a feasibility test and field test at the Shulin Arts Comprehensive Administration Building in Taiwan. The results showed that the proposed method changes the traditional information delivery between users and the facility management platform. By integrating natural language processing (NLP), building information modelling (BIM), and ontological techniques, the proposed method can increase the efficiency of FM information retrieval.

Comparable outcomes of recycled autografts and allografts for reconstructions in patients with high-grade osteosarcoma.

PURPOSE: This retrospective, single-centre study compares the clinical and radiographic outcomes of limb reconstruction using recycled autografts to that using allografts. METHODS: Patients with histopathologically verified high-grade osteosarcoma treated with wide bone resection and limb reconstruction using allografts or recycled autografts from January 1998 through December 2012 were retrospectively screened for enrolment eligibility. The final study cohort included 255 patients (allograft, 91; recycled autograft, 164). Data regarding post-operative complications, salvage treatment, and graft survival were collected. A modified International Society of Limb Salvage classification system was used to evaluate the radiographic findings. RESULTS: The time to graft-host union did not differ significantly between the two graft types. Patients receiving recycled autografts had fewer complications compared than did those receiving allografts (recycled autografts vs. allograft: structural failure, 4.3 vs. 13.2%; late infection, 2.4 vs. 7.7%; all p < 0.05). Complications occurred most frequently during the first three years after surgery, and the majority were manageable. The five year limb survival rate did not differ significantly between the two graft types (91.3 vs. 94.0%; p = 0.752). No local oncological recurrence was observed within the recycled autografts. CONCLUSION: Recycled autografts and allografts are feasible options for biological limb reconstructions in terms of complications and graft survival after wide resection of osteosarcoma.

Psychometric Properties and Efficiency of the Computerized Adaptive Testing System for Measuring Self-Care Performance in Taiwanese Children With Developmental Disabilities.

OBJECTIVE: To investigate the psychometric properties and efficiency of the computerized adaptive testing system for measuring self-care performance (CAT-SC). The psychometric properties included intrarater and interrater reliabilities, concurrent validity, minimal detectable change, minimal important difference, and responsiveness. DESIGN: Criterion standard study. SETTING: A teaching hospital. PARTICIPANTS: A convenience sample of 60 caregivers of children with developmental disabilities was recruited at the initial assessment, and 95% of the children (N=57) were followed-up at 3 and 6 months. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The CAT-SC and the Pediatric Evaluation of Disability Inventory Chinese version were used at the initial assessment. We assessed the CAT-SC and asked caregivers to rate children's changes in self-care performance with a separate question rated on a 15-point Likert-type scale at the 3- and 6-month follow-ups. RESULTS: The CAT-SC had excellent intrarater and interrater reliabilities (intraclass coefficient=0.99 and 0.92, respectively), high concurrent validity with the Pediatric Evaluation of Disability Inventory (r=0.91-0.92), and trivial to small responsiveness at 3- and 6-month follow-ups (effect size=0.02 and 0.12, standardized response mean=0.08 and 0.33). The minimal detectable change of intrarater reliabilities and the minimal important difference at the first follow-up were 0.22 and 0.17 logits, respectively. The administration time of the CAT-SC was about 5 minutes. CONCLUSIONS: The results of our study validated the sound psychometric properties and good efficiency of the CAT-SC. Moreover, the values of the minimal detectable change and minimal smallest change can be used as a reference for clinicians and caregivers to interpret children's progress.

Crystal structure of the C-terminal domain of the primosomal DnaT protein: Insights into a new oligomerization mechanism.

DnaT is a replication restart primosomal protein required for re-initiating chromosomal DNA replication in bacteria. DnaT can be a monomer, dimer, trimer, tetramer, or pentamer. The oligomerization and disassembly of DnaT oligomers are critical in primosome assembly. Prior to this work, only the ssDNA-bound structure of the pentameric DnaT truncated protein (aa 84-153; DnaT84-153) was available. The mechanism by which DnaT oligomerizes as different states is unclear. In this paper, we report the crystal structure of the C-terminal domain of DnaT (aa 84-179; DnaTc) at 2.30 Šresolution (PDB entry 6AEQ). DnaTc forms a dimer both in the crystalline state and in solution. As compared with the ssDNA-bound structure of the pentameric DnaT84-153, their subunit-subunit interfaces significantly differ. The different oligomeric architecture suggests a strong conformational change possibly induced by ssDNA. Superposition analysis further indicated that the monomer of a DnaTc dimer shifted away by a distance of 7.5 Šand rotated by an angle of 170° for binding to ssDNA. Basing from these molecular evidence, we discussed and proposed a working model to explain how DnaTc oligomerizes through residue R146 mediation.

Association Between Executing Theory of Mind in a Limited Experimental Context and Executing It in Daily Contexts in Children With Autism Spectrum Disorder: A Cross-Sectional Study.

IMPORTANCE: Theory of mind (ToM) can be divided into two constructs: capacity and performance. Although severity of autism traits and verbal comprehension have been identified as being associated with ToM capacity, no study has yet verified their role in predicting the ToM performance of children with autism spectrum disorder (ASD). OBJECTIVE: To examine the differences and associations between ToM capacity and ToM performance and to verify the role of autism traits and verbal comprehension in predicting ToM performance in children with ASD. DESIGN: Cross-sectional study. SETTING: Pediatric rehabilitation hospitals and clinics. PARTICIPANTS: One hundred four children with ASD who met the inclusion criteria. OUTCOMES AND MEASURES: We examined ToM capacity and ToM performance with the Theory of Mind Task Battery (ToMTB) and the Theory of Mind Inventory-2-Chinese version (ToMI-2-C). Severity of autism traits and verbal comprehension were assessed with the Social Responsiveness Scale, Second Edition (SRS-2), and the Verbal Comprehension Index (VCI) of either the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition or the Wechsler Intelligence Scale for Children-Fourth Edition. We conducted correlation and hierarchical regression analyses. RESULTS: Scores on the ToMI-2-C were significantly correlated with those on the ToMTB, SRS-2, and VCI (rs = .613, -.344, and .566, respectively; p < .01). CONCLUSIONS AND RELEVANCE: ToM capacity is significantly correlated with ToM performance. Both severity of autism traits and verbal comprehension played an important role in predicting ToM performance of children with ASD after controlling for ToM capacity. WHAT THIS ARTICLE ADDS: ToM capacity, severity of autism traits, and verbal comprehension were all significant predictors of ToM performance. Improving ToM capacity, severity of autism traits, and verbal comprehension of children with ASD would be beneficial to their ToM performance.

Upregulation of PRMT6 by LPS suppresses Klotho expression through interaction with NF-κB in glomerular mesangial cells.

Lipopolysaccharide (LPS) released from gram-negative bacteria stimulates immune responses in infected cells. Epigenetic modifications such as DNA methylation and protein methylation modulate LPS-induced innate immune gene expressions. Expression of the Klotho protein decreased with LPS treatment in rats. In a cellular model, information regarding the effect of LPS on Klotho expression was meager. In the present study, we demonstrated that LPS triggered global DNA and protein methylation in glomerular mesangial MES-13 cells. LPS upregulated protein expressions of enzymes central to cellular methylation reactions, especially protein arginine methyltransferase 6 (PRMT6) in MES-13 cells. Expression of the Klotho protein was diminished by LPS and was restored by 5-Aza-2'-deoxycytidine (5-Aza-2'-dc), AMI-1, and ammonium pyrrolidinedithiocarbamate (PDTC), but not adenosine aldehyde (AdOx). NF-κB was identified as a substrate for arginine methylation and interacted with PRMT6 in MES-13 cells. Inhibition of PRMT activity by AMI-1 blocked LPS-induced NF-κB nuclear translocation in MES-13 cells. Our data indicate that NF-κB negatively regulated Klotho expression with an interaction with PRMT6, which was upregulated by LPS in MES-13 cells.

Synthesis and Photophysical Characterization of 2,3-Dihydroquinolin-4-imines: New Fluorophores with Color-Tailored Emission.

In this study, a series of variously substituted 2,3-dihydroquinolin-4-imines (DQIs) were synthesized from N-substituted propargylanilines by copper(I)-catalyzed annulation. The approach adopted in this study under mild, effective conditions exhibited broad substrate tolerance, particularly for functional groups substituted on anilines. Most of the DQI derivatives synthesized under optimal conditions were obtained in good isolated yields of 63-88 %. 2,3-Dihydroquinolinimine thus obtained was easily converted to important structures like 2,3-dihydroquinolone and tetrahydrobenzodiazepin-5-one, confirming the importance of this strategy in constructing various heterocycles. Surprisingly, 2,3-dihydroquinolinimines thus obtained exhibited bright fluorescence with quantum yields up to 66 %. The density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations were performed for understanding the excited-state nature of DQI system. Accordingly, a tailored DQI derivative bearing methoxy group at C-6 position and acetoxy group at C-7 position was designed and synthesized to give emission at 559 nm with redshift compared to the 7-methoxy substituted DQI. A detailed study of DQI structures with their photophysical properties was performed with five control molecules and consequently demonstrated the uniqueness of the chemical structures of DQIs.