The development of inducible bronchus-associated lymphoid tissue depends on IL-17.

Ectopic or tertiary lymphoid tissues, such as inducible bronchus-associated lymphoid tissue (iBALT), form in nonlymphoid organs after local infection or inflammation. However, the initial events that promote this process remain unknown. Here we show that iBALT formed in mouse lungs as a consequence of pulmonary inflammation during the neonatal period. Although we found CD4(+)CD3(-) lymphoid tissue-inducer cells (LTi cells) in neonatal lungs, particularly after inflammation, iBALT was formed in mice that lacked LTi cells. Instead, we found that interleukin 17 (IL-17) produced by CD4(+) T cells was essential for the formation of iBALT. IL-17 acted by promoting lymphotoxin-α-independent expression of the chemokine CXCL13, which was important for follicle formation. Our results suggest that IL-17-producing T cells are critical for the development of ectopic lymphoid tissues.

Genetic Correlation of miRNA Polymorphisms and STAT3 Signaling Pathway with Recurrent Implantation Failure in the Korean Population.

The growing prevalence of in vitro fertilization-embryo transfer procedures has resulted in an increased incidence of recurrent implantation failure (RIF), necessitating focused research in this area. STAT3, a key factor in maternal endometrial remodeling and stromal proliferation, is crucial for successful embryo implantation. While the relationship between STAT3 and RIF has been studied, the impact of single nucleotide polymorphisms (SNPs) in miRNAs, well-characterized gene expression modulators, on STAT3 in RIF cases remains uncharacterized. Here, we investigated 161 RIF patients and 268 healthy control subjects in the Korean population, analyzing the statistical association between miRNA genetic variants and RIF risk. We aimed to determine whether SNPs in specific miRNAs, namely miR-218-2 rs11134527 G>A, miR-34a rs2666433 G>A, miR-34a rs6577555 C>A, and miR-130a rs731384 G>A, were significantly associated with RIF risk. We identified a significant association between miR-34a rs6577555 C>A and RIF prevalence (implantation failure [IF] ≥ 2: adjusted odds ratio [AOR] = 2.264, 95% CI = 1.007-5.092, p = 0.048). These findings suggest that miR-34a rs6577555 C>A may contribute to an increased susceptibility to RIF. However, further investigations are necessary to elucidate the precise mechanisms underlying the role of miR-34a rs6577555 C>A in RIF. This study sheds light on the genetic and molecular factors underlying RIF, offering new avenues for research and potential advancements in the diagnosis and treatment of this complex condition.

The teaching of geriatric dentistry in South Korean dental schools.

OBJECTIVE: The purpose of this study was to investigate the curriculum of geriatric dentistry for undergraduates in Korean dental schools. BACKGROUND: For development purposes, it was necessary to compare geriatric dentistry education programmes in South Korea to programmes in the United States and Europe. METHODS: The most recent curriculum and related information on geriatric dentistry at the undergraduate level in all 11 dental schools in South Korea were collected by both official letter and e-mail. A symposium for gathering expert opinions to improve geriatric dentistry education in South Korea was also held. The collected data were analysed, and the expert opinions at the symposium were summarised. RESULTS: Six of 11 schools had a didactic course as compulsory and three schools as elective. The course was usually conducted as a form of integrated lectures, and the level of standardisation of lecture content was very low. There were no topics for older people who cannot access dental clinics due to functional frailty or disability. No dental school-affiliated hospitals had an independent department for geriatric dentistry. No schools provided clinical teaching for geriatric dentistry. There were no outreach programmes for geriatric dentistry. CONCLUSIONS: The educational curriculum for geriatric dentistry in South Korea was insufficient to cope with social and demographic changes. Curriculum content should include clinical practice education and needs to be focused on frail and dependent older adult patients. An essential educational curriculum and core competency for geriatric dentistry should be prepared.

Superior Capsular Reconstruction Using Acellular Dermal Allograft Combined With Remaining Rotator Cuff Augmentation Improved Shoulder Pain and Function at 1 Year After The Surgery.

PURPOSE: The purpose of this study is to report structural integrity and clinical outcomes of superior capsular reconstruction (SCR) using a 4- to 5-mm acellular dermal allograft combined with augmentation of the remaining rotator cuff to the graft. METHODS: We prospectively recruited 21 patients with symptomatic irreparable rotator cuff tear who required SCR. At least 6 months after the SCR, we evaluated each patient's graft healing by magnetic resonance imaging (MRI). We also assessed the range of motion (ROM), strength for forward flexion and external rotation, visual analog scale for pain (PVAS), American Shoulder and Elbow Surgeon (ASES) score, and Constant score. At minimum of 1 year after the surgery, we evaluated the number of patients with minimal clinically important differences (MCIDs) for each score to compare patients with healed and unhealed grafts. RESULTS: Postoperative MRI showed the grafts intact in 14 patients (66.7%). Among 7 patients with unhealed grafts, tears were observed in 3 patients (42.9%) on the glenoid side, 3 (42.9%) on the humeral side, and 1 (14.3%) on both sides. PVAS, ASES score, and the Constant score improved after surgery (4.0 to 0.7 for PVAS [P < .001], 55.5 to 87.0 for ASES score [P < .001], and 56.0 to 65.9 for Constant score [P = .007]). However, there were no differences in postoperative ROM and muscle strength compared to preoperative measurements. MCIDs were reached in 90.5% of patients (n = 19) for the PVAS and in 71.4% of patients (n = 15) for the ASES score. Only 33.3% of patients (n = 7) obtained MCIDs for the Constant score, and none of the patients with a graft tear obtained MCIDs in the Constant score (P = .047). CONCLUSION: The graft complete healing rate was 66.7%, although pain relief and functional improvement were satisfactory regardless of graft structural integrity. However, muscle strength recovery was not optimal until 1 year after surgery. LEVEL OF EVIDENCE: Level IV; case series.

Tear pattern after superior capsular reconstruction using an acellular dermal matrix allograft.

BACKGROUND: The healing rate and tear pattern of grafts in superior capsular reconstruction (SCR) using acellular dermal matrix (ADM) allograft are poorly understood, and clinical results based on the graft status remain controversial. METHODS: Fifty-one consecutive patients undergoing arthroscopic SCR with ADM between October 2017 and February 2020 were enrolled. Range of motion, strength, and the visual analog scale pain (PVAS) score, American Shoulder and Elbow Surgeons (ASES) score, and Constant score were evaluated preoperatively and at the last follow-up. Postoperative magnetic resonance imaging was performed in all patients and was obtained at least 6 months (mean, 8.9 ± 3.6 months) after surgery. The graft tear status was analyzed on magnetic resonance imaging, and the numbers of patients who achieved the minimal clinically important difference and patient acceptable symptomatic state were analyzed to determine the differences in outcome according to graft tear status. RESULTS: The range of motion and clinical results improved at a minimum of 1 year (mean, 18 ± 5.4 months), whereas strength in forward flexion and external rotation did not (P = .676 and P = .995, respectively). The graft was intact in 36 of 51 patients (70.6%), 9 patients (17.6%) showed an incomplete graft tear with maintained continuity (partial graft rupture at 1 anchor on either the glenoid or humeral side), and 6 patients (11.8%) showed complete graft rupture (5 on the glenoid side and 1 on the humeral side). In cases with a tear (either incomplete or complete), the odds of achieving the minimal clinically important difference for the PVAS score (P = .047) and ASES score (P = .020) was significantly lower than that of the intact graft. However, when the continuity of the graft was maintained, even in cases with a partial tear, patients who reached the patient acceptable symptomatic state showed significantly higher odds for the PVAS score and trends for the ASES score. CONCLUSION: After SCR using ADM, the graft status could be classified as intact, an incomplete graft tear (where the continuity between the glenoid and humerus was maintained), or an complete tear. When the graft continuity was maintained, even in incomplete graft tears, patients were generally satisfied with postoperative pain and function at 1 year following SCR.

Ethyl Gallate Dual-Targeting PTPN6 and PPARγ Shows Anti-Diabetic and Anti-Obese Effects.

The emergence of the high correlation between type 2 diabetes and obesity with complicated conditions has led to the coinage of the term "diabesity". AMP-activated protein kinase (AMPK) activators and peroxisome proliferator-activated receptor (PPARγ) antagonists have shown therapeutic activity for diabesity, respectively. Hence, the discovery of compounds that activate AMPK as well as antagonize PPARγ may lead to the discovery of novel therapeutic agents for diabesity. In this study, the knockdown of PTPN6 activated AMPK and suppressed adipogenesis in 3T3-L1 cells. By screening a library of 1033 natural products against PTPN6, we found ethyl gallate to be the most selective inhibitor of PTPN6 (Ki = 3.4 µM). Subsequent assay identified ethyl gallate as the best PPARγ antagonist (IC50 = 5.4 µM) among the hit compounds inhibiting PTPN6. Ethyl gallate upregulated glucose uptake and downregulated adipogenesis in 3T3-L1 cells as anticipated. These results strongly suggest that ethyl gallate, which targets both PTPN6 and PPARγ, is a potent therapeutic candidate to combat diabesity.

Phloridzin Acts as an Inhibitor of Protein-Tyrosine Phosphatase MEG2 Relevant to Insulin Resistance.

Inhibition of the megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2, also named PTPN9) activity has been shown to be a potential therapeutic strategy for the treatment of type 2 diabetes. Previously, we reported that PTP-MEG2 knockdown enhances adenosine monophosphate activated protein kinase (AMPK) phosphorylation, suggesting that PTP-MEG2 may be a potential antidiabetic target. In this study, we found that phloridzin, isolated from Ulmus davidiana var. japonica, inhibits the catalytic activity of PTP-MEG2 (half-inhibitory concentration, IC50 = 32 ± 1.06 µM) in vitro, indicating that it could be a potential antidiabetic drug candidate. Importantly, phloridzin stimulated glucose uptake by differentiated 3T3-L1 adipocytes and C2C12 muscle cells compared to that by the control cells. Moreover, phloridzin led to the enhanced phosphorylation of AMPK and Akt relevant to increased insulin sensitivity. Importantly, phloridzin attenuated palmitate-induced insulin resistance in C2C12 muscle cells. We also found that phloridzin did not accelerate adipocyte differentiation, suggesting that phloridzin improves insulin sensitivity without significant lipid accumulation. Taken together, our results demonstrate that phloridzin, an inhibitor of PTP-MEG2, stimulates glucose uptake through the activation of both AMPK and Akt signaling pathways. These results strongly suggest that phloridzin could be used as a potential therapeutic candidate for the treatment of type 2 diabetes.

Fluorinated CRA13 analogues: Synthesis, in vitro evaluation, radiosynthesis, in silico and in vivo PET study.

Fluorine is a unique atom that imparts distinct properties to bioactive molecules upon incorporation. Herein, we prepare and study fluorinated derivatives of the nanomolar affine peripherally restricted dual CB1R/CB2R agonist; CRA13 and its analogs. Binding affinity evaluation relative to CRA13 proved the stronger binding affinity of compound 7c to CB1R and CB2R by 6.95 and 5.64 folds. Physicochemical properties evaluation proved compound 7c improved lipophilicity profile suggesting some enhanced BBB penetration relative to CRA13. Radiosynthesis of 18F-labeled compound 7c was conducted conveniently affording pure hot ligand. In vivo PET study investigation demonstrated efficient distribution of 18F-labeled compound 7c in peripheral tissues visualizing peripheral CB1R/CB2R generating time-activity-curves showing good standard uptake values. Despite enhanced BBB penetration and increased cannabinoid receptors binding affinity, low brain uptake of 7c was observed. In silico docking study explained the measured binding affinities of compounds 7a-d to CB1R. While most of previous efforts aimed to develop central cannabinoid PET imaging agents, 18F-labeled compound 7c might be a promising agent serving as a universal CB1R/CB2R PET imaging agents for diagnosis and therapy of various diseases correlated with peripheral cannabinoid system. It might also serve as a lead compound for development of PET imaging of peripheral and central cannabinoid systems.

Mucin gene polymorphisms are associated with endometriosis in Korean women.

OBJECTIVE: Mucin family members mucin 1 (MUC1) and mucin 4 (MUC4) play an important role in transformation and adhesion, and are known markers for the detection of cancer. However, the pathophysiology of endometriosis associated with the mucin gene is unclear. In this study, we analyzed the relationship between MUC1 and MUC4 single-nucleotide polymorphisms (SNPs) and the risk for endometriosis. METHODS: We performed a case-controlled study of 29 endometriosis clinical samples and 27 functional cysts as control. Sixteen SNPs (rs145224844, rs139620330, rs144273480, rs1611770, rs146141676, rs201798179, rs201815857, rs199840128, rs200788986, rs141460657, rs183700327, rs199768496, rs191544901, rs200639498, rs148332231, and rs11465209) of MUC1 gene and eight SNPs (rs1104760, rs1106502, rs882605, rs2291651, rs2291652, rs2291653, rs2291654, and rs375068067) of the MUC4 gene were identified. We amplified SNP sites by polymerase chain reaction (PCR) using specific primer sets followed by DNA sequencing. RESULTS: The single mutation analysis of MUC4 showed that MUC4 mutations had no effect on the risk for endometriosis, but the frequencies of haplotypes [T/T + T/T + C/C] (rs2291653, 2291654 and rs375068067) were associated with endometriosis. CONCLUSION: The MUC1 genotype may not be correlated with endometriosis susceptibility. However, MUC4 polymorphisms are associated with the risk for endometriosis in Korean women.

QSAR Model for Predicting the Cannabinoid Receptor 1 Binding Affinity and Dependence Potential of Synthetic Cannabinoids.

In recent years, there have been frequent reports on the adverse effects of synthetic cannabinoid (SC) abuse. SCs cause psychoactive effects, similar to those caused by marijuana, by binding and activating cannabinoid receptor 1 (CB1R) in the central nervous system. The aim of this study was to establish a reliable quantitative structure-activity relationship (QSAR) model to correlate the structures and physicochemical properties of various SCs with their CB1R-binding affinities. We prepared tetrahydrocannabinol (THC) and 14 SCs and their derivatives (naphthoylindoles, naphthoylnaphthalenes, benzoylindoles, and cyclohexylphenols) and determined their binding affinity to CB1R, which is known as a dependence-related target. We calculated the molecular descriptors for dataset compounds using an R/CDK (R package integrated with CDK, version 3.5.0) toolkit to build QSAR regression models. These models were established, and statistical evaluations were performed using the mlr and plsr packages in R software. The most reliable QSAR model was obtained from the partial least squares regression method via Y-randomization test and external validation. This model can be applied in vivo to predict the addictive properties of illicit new SCs. Using a limited number of dataset compounds and our own experimental activity data, we built a QSAR model for SCs with good predictability. This QSAR modeling approach provides a novel strategy for establishing an efficient tool to predict the abuse potential of various SCs and to control their illicit use.

Porous Poly(3-hydroxybutyrate) Scaffolds Prepared by Non-Solvent-Induced Phase Separation for Tissue Engineering.

Highly porous poly(3-hydroxybutyrate) (PHB) scaffolds were fabricated using non-solvent-induced phase separation with chloroform as the solvent and tetrahydrofuran as the non-solvent. The microporosity, nanofiber morphology, and mechanical strength of the scaffolds were adjusted by varying the fabrication parameters, such as the polymer concentration and solvent composition. The influence of these parameters on the structure and morphology of PHB organogels and scaffolds was elucidated using small-angle neutron scattering and scanning electron microscopy. The organogels and scaffolds in this study have a complex hierarchical structure, extending over a wide range of length scales. In vitro viability assays were performed using the human keratinocyte cell line (HaCaT), and all PHB scaffolds demonstrated the excellent cell viability. Microporosity had the greatest impact on HaCaT cell proliferation on PHB scaffolds, which was determined after a 3-day incubation period with scaffolds of different morphologies and mechanical properties. The superior cell viability and the controlled scaffold properties and morphologies suggested PHB scaffolds fabricated by non-solvent-induced phase separation using chloroform and tetrahydrofuran as promising biomaterials for the applications of tissue engineering, particularly of epidermal engineering. Electronic Supplementary Material: Supplementary material is available in the online version of this article at 10.1007/s13233-020-8109-x.

Correction to: Effect of training on ultrasonography (US) BI-RADS features for radiology residents: a multicenter study comparing performances after training.

The original version of this article, published on 07 January 2019, unfortunately contained a mistake.

Effect of training on ultrasonography (US) BI-RADS features for radiology residents: a multicenter study comparing performances after training.

OBJECTIVES: To evaluate the effect of training radiology residents on breast ultrasonography (US) according to the Breast Imaging Reporting And Data System (BI-RADS) and the factors that influence the training effect. METHODS: This multicenter, prospective study was approved by eight institutional review boards. From September 2013 to July 2014, 248 breast masses in 227 women were included for US image acquisition. Representative B-mode and video images of the breast masses were recorded, among which 54 cases were included in the education set and 66 in the test set. Sixty-one radiology residents scheduled for breast imaging training individually reviewed the test set, immediately before, 1 month after, and 6 months after training. Diagnostic performances and US descriptors of the residents were evaluated and compared against those of expert radiologists. RESULTS: Agreements between residents and experienced radiologists showed improvement after training, while agreements between post-training and post-6-month training descriptors did not show significant differences (all p > 0.05, respectively). Sensitivity, negative predictive value (NPV), and AUC were significantly improved for residents post-training and post-6-month training (all p < 0.05), while approximating the performances of expert radiologists except for AUC (0.836, 0.840, and 0.908, respectively, p < 0.05). Low levels of pre-training AUC, total number of breast US examinations, and the number of sessions per week that residents were involved in were factors influencing the improvement of AUC. CONCLUSION: Training using education material dedicated for breast US imaging effectively improved the diagnostic performances of radiology residents and agreements with experienced radiologists on US BI-RADS features. KEY POINTS: • Agreements on lesion descriptors between residents and experienced radiologists showed improvement after training, regardless of test point. • Sensitivity, NPV, and AUC were significantly improved for residents in post-training and post-6-month training (all p < 0.05). • Low levels of pre-training AUC, total number of breast US examinations, and the number of sessions per week that residents were involved in were factors influencing the improvement of AUC.

Identification of chebulinic acid as a dual targeting inhibitor of protein tyrosine phosphatases relevant to insulin resistance.

Natural products as antidiabetic agents have been shown to stimulate insulin signaling via the inhibition of the protein tyrosine phosphatases relevant to insulin resistance. Previously, we have identified PTPN9 and DUSP9 as potential antidiabetic targets and a multi-targeting natural product thereof. In this study, knockdown of PTPN11 increased AMPK phosphorylation in differentiated C2C12 muscle cells by 3.8 fold, indicating that PTPN11 could be an antidiabetic target. Screening of a library of 658 natural products against PTPN9, DUSP9, or PTPN11 identified chebulinic acid (CA) as a strong allosteric inhibitor with a slow cooperative binding to PTPN9 (IC50 = 34 nM) and PTPN11 (IC50 = 37 nM), suggesting that it would be a potential antidiabetic candidate. Furthermore, CA stimulated glucose uptake and resulted in increased AMP-activated protein kinase (AMPK) phosphorylation. Taken together, we demonstrated that CA increased glucose uptake as a dual inhibitor of PTPN9 and PTPN11 through activation of the AMPK signaling pathway. These results strongly suggest that CA could be used as a potential therapeutic candidate for the treatment of type 2 diabetes.

Parity: a risk factor for decreased pelvic floor muscle strength and endurance in middle-aged women.

INTRODUCTION AND HYPOTHESIS: The incidence of pelvic floor muscle (PFM) dysfunction increases rapidly with menopause and aging. Despite the raised magnitude and prevalence of pelvic floor disorders in middle-aged women, the risk factors underlying PFM dysfunction still remain to be identified. PFM function can be clinically measured as the maximum strength and endurance using manometry. The aim of this study was to evaluate PFM function in terms of strength and endurance by perineometer and to assess the risk factors that decrease PFM strength and endurance in middle-aged women. METHODS: This was a cross-sectional study. Overall, 125 parous women (age 40-60 years) completed the study. A questionnaire was used to collect information on several demographic and obstetric variables. The Peritron perineometer measured PFM strength and endurance. Multiple linear regression analysis was used to evaluate the effects of sociodemographic variables on PFM function. RESULTS: Both average strength of PFMs and maximum muscle strength significantly reduced as the number of parity increased. Average and maximum strength of PFMs showed a significant difference between women with parities of two and one (ß = -0.435, p < .001; ß = -0.441, p < 0.001, respectively). Both were even more influenced in women with parity of three (ß = -0.503, p < .001; ß = -0.500, p < .001). However, PFM endurance did not decrease with increasing parity number until the parity of two; however, it decreased in women with parity of three (ß = -0.302, p < 0.05). CONCLUSION: Parity appeared to have a dominant influence on weakness of PFM, and strength was more significantly associated with parity than endurance in middle-aged women.

Comparison of the SRmax, SRave, and color map of strain-elastography in differentiating malignant from benign breast lesions.

BACKGROUND: The maximum value of the strain ratio (SR) is a newly developed measure in strain-elastography. PURPOSE: To prospectively compare the diagnostic performance of three different measures of strain-elastography, the maximum value of the SR (SRmax), the average value of the SR (SRave), and the color map, for differentiating benign and malignant breast lesions. MATERIAL AND METHODS: We obtained the SRmax and SRave of 314 lesions from 290 patients with the tissue to nodule SR and color map using a five-degree scoring system. The diagnostic performances of the SRmax, SRave, and color map were compared after obtaining the area under the receiver operating characteristic (ROC) curves (AUCs) of each parameter. RESULTS: The AUC of the SRmax (0.7674) was larger than the AUCs of the SRave (0.7138) and color map (0.6324), with statistical significance ( P = 0.0383 for SRmax vs. SRave, P = 0.0000 for SRmax vs. color map). The AUC of the SRave was larger than that of the color map; however, there was no significant difference. The optimal cut-off point of the SRmax that balanced the sensitivity (91.12%) and specificity (50.81%) was 5.16. CONCLUSION: The SRmax is a more reliable diagnostic tool than the SRave and color map for differentiating benign and malignant breast lesions.

ORESARA15 Acts Synergistically with ANGUSTIFOLIA3 and Separately from AINTEGUMENTA to Promote Cell Proliferation during Leaf Growth.

Developing leaves undergo sequential coordinated cell proliferation and cell expansion to determine their final size and shape. Although several important regulators of cell proliferation have been reported, the gene network regulating leaf developmental processes remains unclear. Previously, we showed that ORESARA15 (ORE15) positively regulates the rate and duration of cell proliferation by promoting the expression of direct targets, GROWTH-REGULATING FACTOR (GRF) transcription factors, during leaf growth. In the current study, we examined the spatiotemporal patterns of ORE15 expression and determined that ORE15 expression partially overlapped with AN3/GIF1 and ANT expression along the midvein in the proximal region of the leaf blade in young leaves. Genetic analysis revealed that ORE15 may function synergistically with AN3 to control leaf growth as a positive regulator of cell proliferation. Our molecular and genetic studies are the first to suggest the importance of functional redundancies between ORE15 and AN3, and between AN3 and ANT in cell proliferation regulatory pathway during leaf growth.

Red Ginseng Attenuates Aß-Induced Mitochondrial Dysfunction and Aß-mediated Pathology in an Animal Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by neurodegeneration and cognitive deficits. Amyloid beta (Aß) peptide is known to be a major cause of AD pathogenesis. However, recent studies have clarified that mitochondrial deficiency is also a mediator or trigger for AD development. Interestingly, red ginseng (RG) has been demonstrated to have beneficial effects on AD pathology. However, there is no evidence showing whether RG extract (RGE) can inhibit the mitochondrial deficit-mediated pathology in the experimental models of AD. The effects of RGE on Aß-mediated mitochondrial deficiency were investigated in both HT22 mouse hippocampal neuronal cells and the brains of 5XFAD Aß-overexpressing transgenic mice. To examine whether RGE can affect mitochondria-related pathology, we used immunohistostaining to study the effects of RGE on Aß accumulation, neuroinflammation, neurodegeneration, and impaired adult hippocampal neurogenesis in hippocampal formation of 5XFAD mice. In vitro and in vivo findings indicated that RGE significantly improves Aß-induced mitochondrial pathology. In addition, RGE significantly ameliorated AD-related pathology, such as Aß deposition, gliosis, and neuronal loss, and deficits in adult hippocampal neurogenesis in brains with AD. Our results suggest that RGE may be a mitochondria-targeting agent for the treatment of AD.

ORESARA15, a PLATZ transcription factor, mediates leaf growth and senescence in Arabidopsis.

Plant leaves undergo a series of developmental changes from leaf primordium initiation through growth and maturation to senescence throughout their life span. Although the mechanisms underlying leaf senescence have been intensively elucidated, our knowledge of the interrelationship between early leaf development and senescence is still fragmentary. We isolated the oresara15-1Dominant (ore15-1D) mutant, which had an extended leaf longevity and an enlarged leaf size, from activation-tagged lines of Arabidopsis. Plasmid rescue identified that ORE15 encodes a PLANT A/T-RICH SEQUENCE- AND ZINC-BINDING PROTEIN family transcription factor. Phenotypes of ore15-1D and ore15-2, a loss-of-function mutant, were evaluated through physiological and anatomical analyses. Microarray, quantitative reverse transcription polymerase chain reaction, and chromatin immunoprecipitation as well as genetic analysis were employed to reveal the molecular mechanism of ORE15 in the regulation of leaf growth and senescence. ORE15 enhanced leaf growth by promoting the rate and duration of cell proliferation in the earlier stage and suppressed leaf senescence in the later stage by modulating the GROWTH-REGULATING FACTOR (GRF)/GRF-INTERACTING FACTOR regulatory pathway. Our study highlighted a molecular conjunction through ORE15 between growth and senescence, which are two temporally separate developmental processes during leaf life span.

Synthesis of oxidative metabolites of CRA13 and their analogs: Identification of CRA13 active metabolites and analogs thereof with selective CB2R affinity.

CRA13; a peripheral dual CB1R/CB2R agonist with clinically proven analgesic properties, infiltrates into CNS producing adverse effects due to central CB1R agonism. Such adverse effects might be circumvented by less lipophilic compounds with attenuated CB1R affinity. Metabolism produces less lipophilic metabolites that might be active metabolites. Some CRA13 oxidative metabolites and their analogues were synthesized as less lipophilic CRA13 analogues. Probing their CB1R and CB2R activity revealed the alcohol metabolite 8c as a more potent and more effective CB2R ligand with attenuated CB1R affinity relative to CRA13. Also, the alcohol analogue 8b and methyl ester 12a possessed enhanced CB2R affinity and reduced CB1R affinity. The CB2R binding affinity of alcohol analogue 8b was similar to CRA13 while that of methyl ester 12a was more potent. In silico study provided insights into the possible molecular interactions that might explain the difference in the elicited biological activity of these compounds.