Highly Efficient Blue Fluorescent Organic Light-Emitting Devices Based on λ5-Phosphinine Derivatives.

Although λ5-phosphinine derivatives are known as a promising class of blue fluorescent emitters, those photoluminescent quantum yield (PLQY) values have been reached up to 92 %, however, only a few examples have been explored as an emitter for blue organic light-emitting device (OLED), and the external quantum efficiency (EQE) has been below 2.4 % so far. In this study, we newly developed two types of blue λ5-phosphinine derivatives namely CN-COCF3 and CO2Me-CHO, and investigated the photophysical properties in the solid states. The photophysical analyses in solid state films suggested that the strong electron-accepting nature of these λ5-phosphinine derivatives caused the inferior PLQY values, and the exciplex formation with the host and neighboring materials should be avoided to improve the device efficiency. By choosing suitable host and neighboring materials with deep ionization potentials, we successfully realized efficient blue fluorescent OLEDs with EQE of over 4 % and CIE (0.14, 0.18). This is among the best in λ5-phosphinine-based blue OLEDs so far.

PRC1 suppresses a female gene regulatory network to ensure testicular differentiation.

Gonadal sex determination and differentiation are controlled by somatic support cells of testes (Sertoli cells) and ovaries (granulosa cells). In testes, the epigenetic mechanism that maintains chromatin states responsible for suppressing female sexual differentiation remains unclear. Here, we show that Polycomb repressive complex 1 (PRC1) suppresses a female gene regulatory network in postnatal Sertoli cells. We genetically disrupted PRC1 function in embryonic Sertoli cells after sex determination, and we found that PRC1-depleted postnatal Sertoli cells exhibited defective proliferation and cell death, leading to the degeneration of adult testes. In adult Sertoli cells, PRC1 suppressed specific genes required for granulosa cells, thereby inactivating the female gene regulatory network. Chromatin regions associated with female-specific genes were marked by Polycomb-mediated repressive modifications: PRC1-mediated H2AK119ub and PRC2-mediated H3K27me3. Taken together, this study identifies a critical Polycomb-based mechanism that suppresses ovarian differentiation and maintains Sertoli cell fate in adult testes.

Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding.

Mutations of G protein-coupled receptors (GPCRs) cause various human diseases, but the mechanistic details are limited. Here, we establish p.E303K in the gene encoding the endothelin receptor type A (ETAR/EDNRA) as a recurrent mutation causing mandibulofacial dysostosis with alopecia (MFDA), with craniofacial changes similar to those caused by p.Y129F. Mouse models carrying either of these missense mutations exhibited a partial maxillary-to-mandibular transformation, which was rescued by deleting the ligand endothelin 3 (ET3/EDN3). Pharmacological experiments confirmed the causative ETAR mutations as gain of function, dependent on ET3. To elucidate how an amino acid substitution far from the ligand binding site can increase ligand affinity, we used molecular dynamics (MD) simulations. E303 is located at the intracellular end of transmembrane domain 6, and its replacement by a lysine increased flexibility of this portion of the helix, thus favoring G protein binding and leading to G protein-mediated enhancement of agonist affinity. The Y129F mutation located under the ligand binding pocket reduced the sodium-water network, thereby affecting the extracellular portion of helices in favor of ET3 binding. These findings provide insight into the pathogenesis of MFDA and into allosteric mechanisms regulating GPCR function, which may provide the basis for drug design targeting GPCRs.

Constructing Soluble Anthracene-Based Blue Emitters Free of Electrically Inert Alkyl Chains for Efficient Evaporation- and Solution-Based OLEDs.

Anthracene derivatives are one of the most promising blue emitters employed in organic light-emitting devices (OLEDs) because of their electrochemical and thermal stabilities. However, their high crystallinity owing to their large π-planar structures severely impedes the progress in the development of solution-based systems. In this work, we developed two types of highly soluble multifunctional anthracene derivatives terminated with ortho-biphenyl and triphenylamine moieties and showed high solubility in general organic solvents such as toluene, tetrahydrofuran, and cyclohexanone at high concentrations (>10 mg mL-1 ), and showed blue emission with a peak wavelength of ∼465 nm and a high photoluminescence quantum yield that ranges up to 81 %. Notably, these emitters are suitable for fabricating both evaporation- and solution-based systems. The evaporation-based system OLED achieved a high external quantum efficiency (EQE) of 5.4 %. While the solution-processed system realized 4.8 %, exhibiting the best performance among the anthracene-based solution-processed OLEDs so far.

Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients.

OBJECTIVES: Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000-3000 years. METHODS: Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. RESULTS: In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10-8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients' gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. CONCLUSIONS: Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.

A novel mode of DnaA-DnaA interaction promotes ADP dissociation for reactivation of replication initiation activity.

ATP-DnaA is temporally increased to initiate replication during the cell cycle. Two chromosomal loci, DARS (DnaA-reactivating sequences) 1 and 2, promote ATP-DnaA production by nucleotide exchange of ADP-DnaA for timely initiation. ADP-DnaA complexes are constructed on DARS1 and DARS2, bearing a cluster of three DnaA-binding sequences (DnaA boxes I-III), promoting ADP dissociation. Although DnaA has an AAA+ domain, which ordinarily directs construction of oligomers in a head-to-tail manner, DnaA boxes I and II are oriented oppositely. In this study, we constructed a structural model of a head-to-head dimer of DnaA AAA+ domains, and analyzed residues residing on the interface of the model dimer. Gln208 was specifically required for DARS-dependent ADP dissociation in vitro, and in vivo analysis yielded consistent results. Additionally, ADP release from DnaA protomers bound to DnaA boxes I and II was dependent on Gln208 of the DnaA protomers, and DnaA box III-bound DnaA did not release ADP nor require Gln208 for ADP dissociation by DARS-DnaA complexes. Based on these and other findings, we propose a model for DARS-DnaA complex dynamics during ADP dissociation, and provide novel insight into the regulatory mechanisms of DnaA and the interaction modes of AAA+ domains.

Prediction of the operative time for hysteroscopic myomectomy for leiomyomas penetrating the intramural cavity using leiomyoma weight and clinical characteristics of patients.

PURPOSE: To preoperatively predict the operative time (OT) for hysteroscopic myomectomy for G1 or G2 leiomyoma based on leiomyoma weight. METHODS: The data from 544 patients who underwent one-step hysteroscopic myomectomy were analyzed retrospectively. A total of 340 patients with leiomyoma penetrating the intramural cavity were identified as suitable candidates for calculation of the OT based on leiomyoma weight; we considered leiomyoma weight to be the most objective parameter for evaluating leiomyoma tissues. Additionally, 460 patients with a single leiomyoma were analyzed to estimate the weight of the resected leiomyoma based on its diameter. RESULTS: Considering total leiomyoma weight (TLW) and two additional coefficients (1.5: G2 leiomyoma, 0.75: vaginal parity of the patient), we demonstrated that our formula correlated well with OT (R 2 = 0.72). TLW also correlated well with the cube of the average diameter (AD) of leiomyomas (R 2 = 0.89). Predicting TLW significantly improved the application of specific coefficients depending on its value (1.0: AD 0.1-2.0 cm, 0.8: AD 2.1-3.0 cm, 0.7: AD 3.1-5.7 cm). CONCLUSION: The OT for hysteroscopic myomectomy of intracavital leiomyoma can be predicted prior to surgery using simple clinical information of the target leiomyoma and the patient.

Utility of a minimal skin incision laparotomy technique for removing uterine leiomyomas at a regional core hospital: a retrospective study.

BACKGROUND: We present a minimal skin wound abdominal myomectomy performed in our hospital and attempt to identify the optimal range of this technique by considering the characteristics of target leiomyomas. In this procedure, we attempted to make the skin wound as small as possible, with a maximum length of approximately 5 cm. METHODS: In addition to introducing the minimal skin wound abdominal myomectomy, we retrospectively collected and analyzed the medical records of 76 patients treated with minimal skin wound abdominal myomectomy exclusively by the same physician at Maruyama Memorial General Hospital between January 2007 and December 2016. We statistically investigated relationships between ten factors, including body mass index; patient's age; patient's parity; administration of gonadotropin-releasing hormone analogue; presence of anemia; the uterine leiomyomas' number, size, weight, and location; operation time; and blood loss. RESULTS: First, we introduce a case in which we performed minimal skin wound abdominal myomectomy for a 36-year-old Japanese patient with a large leiomyoma (10 cm in diameter). Then, we assessed the impacts of patient characteristics and leiomyoma characteristics on operation time and blood loss for this surgical method. In a multivariate analysis, only the number of resected leiomyomas significantly affected massive bleeding. Other factors showed no difference on operation time and the amount of blood loss. CONCLUSIONS: Minimal skin wound abdominal myomectomy is safe and effective for use in many patients, because only the number of leiomyomas affects the amount of blood loss. No other factor affected operation time. We suggest the possibility that the expanded use of minimal skin wound abdominal myomectomy may reduce the number of patients waiting for long periods to undergo laparoscopic surgery and may optimize the use of medical resources in rural areas.