Exploring a ß-Amino Acid with a Seven-Membered Ring Constraint as a Foldamer Building Block for Nontraditional Helices.

We explored trans- and cis-2-aminocycloheptanecarboxylic acid (ACHpC) as potential building blocks for helical foldamers. trans-ACHpC does not show sufficient folding propensity in unnatural peptides. cis-ACHpC promotes nontraditional helices of two unnatural peptide backbones: the 11/9-helix for 1:1 α/ß-peptides and the 12/10-helix for ß-peptides with interconvertible handedness. The two opposite-handed 12/10-helices rapidly interconvert in solution by pseudorotation of the two twist chair forms of the cycloheptane moiety in each cis-ACHpC residue.

Automated hand-marked semantic text recognition from photographs.

Automated text recognition techniques have made significant advancements; however, certain tasks still present challenges. This study is motivated by the need to automatically recognize hand-marked text on construction defect tags among millions of photographs. To address this challenge, we investigated three methods for automating hand-marked semantic text recognition (HMSTR)-a modified scene text recognition-based (STR) approach, a two-step HMSTR approach, and a lumped approach. The STR approach involves locating marked text using an object detection model and recognizing it using a competition-winning STR model. Similarly, the two-step HMSTR approach first localizes the marked text and then recognizes the semantic text using an image classification model. By contrast, the lumped approach performs both localization and identification of marked semantic text in a single step using object detection. Among these approaches, the two-step HMSTR approach achieved the highest F1 score (0.92) for recognizing circled text, followed by the STR approach (0.87) and the lumped approach (0.78). To validate the generalizability of the two-step HMSTR approach, subsequent experiments were conducted using check-marked text, resulting in an F1 score of 0.88. Although the proposed methods have been tested specifically with tags, they can be extended to recognize marked text in reports or books.

Development and Evaluation of Self-Microemulsifying Drug Delivery System for Improving Oral Absorption of Poorly Water-Soluble Olaparib.

The purpose of this study is to develop and evaluate a self-microemulsifying drug delivery system (SMEDDS) to improve the oral absorption of poorly water-soluble olaparib. Through the solubility test of olaparib in various oils, surfactants and co-surfactants, pharmaceutical excipients were selected. Self-emulsifying regions were identified by mixing the selected materials at various ratios, and a pseudoternary phase diagram was constructed by synthesizing these results. The various physicochemical properties of microemulsion incorporating olaparib were confirmed by investigating the morphology, particle size, zeta potential, drug content and stability. In addition, the improved dissolution and absorption of olaparib were also confirmed through a dissolution test and a pharmacokinetic study. An optimal microemulsion was generated in the formulation of Capmul® MCM 10%, Labrasol® 80% and PEG 400 10%. The fabricated microemulsions were well-dispersed in aqueous solutions, and it was also confirmed that they were maintained well without any problems of physical or chemical stability. The dissolution profiles of olaparib were significantly improved compared to the value of powder. Associated with the high dissolutions of olaparib, the pharmacokinetic parameters were also greatly improved. Taken together with the results mentioned above, the microemulsion could be an effective tool as a formulation for olaparib and other similar drugs.

Development of an integrin αv-based universal marker, capable of both prediction and direction of stem cell fate.

Integrin-mediated focal adhesion (FA) and subsequent cytoskeletal reorganization influence cell morphology, migration, and ultimately cell fate. Previous studies have used various patterned surfaces with defined macroscopic cell shapes or nanoscopic FA distributions to explore how different substrates affect the fate of human bone marrow mesenchymal stem cells (BMSCs). However, there is currently no straightforward relationship between BMSC cell fates induced by patterned surfaces and FA distribution substrates. In this study, we conducted single-cell image analysis of integrin αv-mediated FA and cell morphological features of BMSCs during biochemically induced differentiation. This enabled the identification of distinct FA features that can discriminate between osteogenic and adipogenic differentiation, demonstrating that integrin αv-mediated focal adhesion (FA) can be used as a non-invasive biomarker for real time observation. Based on these results, we developed an organized microscale fibronectin (FN) patterned surface where the fate of BMSC could be precisely manipulated by these FA features. Notably, even in the absence of any biochemical inducers, such as those contained in the differentiation medium, BMSCs cultured on these FN patterned surfaces exhibited upregulation of differentiation markers comparable to BMSCs cultured using conventional differentiation methods. Therefore, the present study reveals the application of these FA features as universal markers not only for predicting differentiation status, but also for regulating cell fate by precisely controlling the FA features with a new cell culture platform. STATEMENT OF SIGNIFICANCE: Although the effects of material physiochemical properties on cell morphology and subsequent cell fate decisions have been extensively studied, a simple yet intuitive correlation between cellular features and differentiation remains unavailable. We present a single cell image-based strategy for predicting and directing stem cell fate. By using a specific integrin isoform, integrin αv, we identified distinct geometric features that can be used as a marker for discriminating between osteogenic and adipogenic differentiation in real-time. From these data, new cell culture platforms capable of regulating cell fate by precisely controlling FA features and cell area can be developed.

Predictors of recurrence after total thyroidectomy plus neck dissection and radioactive iodine ablation for high-risk papillary thyroid carcinoma.

BACKGROUND: American Thyroid Association (ATA) proposed management guidelines for differentiated thyroid cancer, including a three-tiered risk stratification system for structural recurrence. This study aimed to compare the various 2015 ATA criteria for the strength of association with the recurrence of high-risk papillary thyroid carcinoma (PTC). STUDY DESIGN: This study included 545 consecutive patients who underwent total thyroidectomy plus neck dissection and radioactive iodine ablation (RAI) for previously untreated high-risk PTC. The association of recurrence-free survival (RFS) with clinicopathological factors was evaluated by univariate and multivariate Cox proportional hazard regression analyses. RESULTS: During a follow-up median period of 89 months, 90 (16.5%) patients had any-site recurrence. Of the high-risk factors, high stimulated thyroglobulin (sTg) level and >3-cm sized lymph nodes (LNs) were significantly associated with recurrence (all P < .005). Sex, tumor size, lymphovascular invasion, multifocality, number of positive LNs, extranodal extension, T and N classifications, and overall tumor-node-metastasis stage were also significantly associated with recurrence (all P < .05). In multivariate analyses, high sTg level [adjusted hazard ratio (HR) = 7.18] and N1b (adjusted HR = 3.27) were independent factors predictive of recurrence (all P ≤ .001). CONCLUSIONS: Postoperative high serum sTg level might be the most important predictor of PTC recurrence after total thyroidectomy plus neck dissection and RAI.

Risk factors for posttreatment recurrence in patients with intermediate-risk papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) is generally associated with favorable outcomes; however, intermediate-risk requires further evaluation. We therefore examined risk factors for posttreatment recurrence in patients with intermediate-risk PTC. METHODS: This study involved 1782 patients who underwent thyroidectomy for intermediate-risk PTC. Univariate and multivariate Cox proportional hazard regression analyses were used to identify the significant factors predictive of posttreatment recurrence-free survival (RFS). RESULTS: Of intermediate-risk factors, univariate analyses showed that clinical and pathological cervical lymph node (LN) positivity (cN1 and pN1), aggressive histology, and multifocality with microscopic extrathyroidal extension were significantly associated with RFS outcomes (all P < 0.05). In multivariate analyses, cN1, >5 pN1, and posttreatment radioactive iodine (RAI)-avid metastatic foci of intermediate risk remained the independent factors predictive of RFS (all P < 0.05). The combination of any three or more of these intermediate-risk factors appeared to increase the posttreatment recurrence rate. CONCLUSION: Clinical nodal positivity, the number of positive LNs, and the presence of RAI-avid metastatic foci in the ATA intermediate-risk category might independently decrease RFS in patients with intermediate-risk PTC.

Fipronil induces apoptosis and cell cycle arrest in porcine oocytes during in vitro maturation.

Fipronil (FPN) is a widely used phenylpyrazole pesticide that can kill pests by blocking γ-aminobutyric acid (GABA)-gated chloride channels. In addition, there are lack of studies on the effects of FPN on the female mammalian gametes. In this study, porcine oocytes were used to investigate the effects of FPN on the oocyte maturation process. The results showed that the first polar body extrusion rate significantly decreased (100 µM FPN vs. control, 18.64 ± 2.95% vs. 74.90 ± 1.50%, respectively), and oocytes were arrested at the germinal vesicle stage in 100 µM FPN group. Meanwhile, the FPN caused a significant increase in reactive oxygen species (ROS) levels and severe DNA damage inside the oocytes. Furthermore, apoptosis was enhanced along with decreases in mitochondrial membrane potential, BCL-xL, and the release of cytochrome C in FPN-treated group. Additionally, low CDK1 activity and delayed cyclin B1 degradation during germinal vesicle breakdown were found in the FPN-treated group, which resulted from the activation of ATM-P53-P21 pathway. In conclusion, FPN induces apoptosis and cell cycle arrest in porcine oocyte maturation because of increased ROS levels and DNA damage. This suggests that the FPN in the environment may have potential detrimental effects on the female mammalian reproductive system.

Acentriolar microtubule organization centers and Ran-mediated microtubule formation pathways are both required in porcine oocytes.

Mammalian oocytes lack centrioles but can generate bipolar spindles using several different mechanisms. For example, mouse oocytes have acentriolar microtubule organization centers (MTOCs) that contain many components of the centrosome, and which initiate microtubule polymerization. On the contrary, human oocytes lack MTOCs and the Ran-mediated mechanisms may be responsible for spindle assembly. Complete knowledge of the different mechanisms of spindle assembly is lacking in various mammalian oocytes. In this study, we demonstrate that both MTOC- and Ran-mediated microtubule nucleation are required for functional meiotic metaphase I spindle generation in porcine oocytes. Acentriolar MTOC components, including Cep192 and pericentrin, were absent in the germinal vesicle and germinal vesicle breakdown stages. However, they start to colocalize to the spindle microtubules, but are absent in the meiotic spindle poles. Knockdown of Cep192 or inhibition of Polo-like kinase 1 activity impaired the recruitment of Cep192 and pericentrin to the spindles, impaired microtubule assembly, and decreased the polar body extrusion rate. When the RanGTP gradient was perturbed by the expression of dominant negative or constitutively active Ran mutants, severe defects in microtubule nucleation and cytokinesis were observed, and the localization of MTOC materials in the spindles was abolished. These results demonstrate that the stepwise involvement of MTOC- and Ran-mediated microtubule assembly is crucial for the formation of meiotic spindles in porcine oocytes, indicating the diversity of spindle formation mechanisms among mammalian oocytes.

Thiamethoxam inhibits blastocyst expansion and hatching via reactive-oxygen species-induced G2 checkpoint activation in pigs.

Thiamethoxam (TMX) is a neonicotinoid insecticide. It has specific high toxicity to insects. Residues of TMX have been detected in various crops. Early embryo quality is vital for fertility. Excessive production of reactive oxygen species (ROS) can override embryonic antioxidant defenses, producing oxidative stress that triggers apoptosis, necrosis, and/or permanent DNA damage responses in the early embryo. Comparative studies have indicated that TMX hepatotoxicity is significant in mammals in acute tests, but little is known about accumulated chronic toxicity in early embryonic development. Porcine embryos were obtained here by the parthenogenetic activation of meiosis II oocytes and cultured in the PZM-5 medium with or without TMX. These embryos were evaluated by various methods. The expansion and hatching of blastocysts treated with TMX decreased by 21.73% and 16.71%, respectively, as compared with controls. In an analysis of 5-bromo-2-deoxyuridine (BrdU) incorporation, the rate of cell proliferation was 44.33% lower as compared with expanded blastocysts of the control group. ROS and γH2AX levels were higher in the TMX group than in the control group. Real-time reverse-transcription polymerase chain reaction showed that Sod1 expression increased and the expression of Mnsod, Gpx1, Igta5, and Cox2 decreased. A CDK1 kinase assay revealed that maturation-promoting factor (MPF) activity diminished by 31.41% in expanding blastocysts. In conclusion, these results suggest that TMX inhibits blastocyst expansion and hatching by ROS-induced DNA damage checkpoint activation, which inhibits the activation of MPF and cell cycle progression in porcine blastocysts.

Initial Nutritional Status and Clinical Outcomes in Patients with Deep Neck Infection.

OBJECTIVES: The current study aims to determine the correlation between nutritional status upon presentation and disease severity, as well as treatment and survival outcomes. METHODS: Patients who were diagnosed with deep neck infection, underwent at least one surgical drainage/debridement, and had more than 1 week of hospitalization at a tertiary medical center from 2007 to 2015 were retrospectively included. Thereafter, initial serum albumin, C-reactive protein (CRP), and body mass index (BMI) were reviewed. RESULTS: A total of 135 patients were included in the final analysis. Accordingly, the proportion of patients with simultaneous mediastinitis (21.0%), necrotizing fasciitis (12.9%), disease extent >1 cervical level (72.6%), mean CRP (22.4 mg/dL), mean length of hospitalization (25.0 days), and mean 1-week follow-up CRP (7.2 mg/dL) was significantly higher in the hypoalbuminemia group (initial serum albumin <3.0 g/dL) than in the normoalbuminemia group (all P<0.05). No significant correlations had been observed according to BMI status. After adjusting for age and Charlson comorbidity index, odds ratios for the following outcomes were calculated in patients initially presenting with hypoalbuminemia: simultaneous mediastinitis (3.07), necrotizing fasciitis (7.89), disease extent >1 cervical level (2.12), initial serum CRP over 20 mg/dL (3.79), hospitalization of more than 14 days (4.10), 1-week follow-up CRP over 5 mg/dL (3.78), and increased duration for an over 50% decrease in initial CRP (2.70) (all P<0.05). Although intravascular albumin replenishment decreased the proportion of patients with hypoalbuminemia after 2 weeks (P<0.05), it did not significantly predict better treatment outcomes. CONCLUSION: Among the markers reflecting an individual's nutritional state, an initial serum albumin of less than 3.0 g/dL was an independent serologic marker predicting increased disease severity and complications in patients with deep neck infection.

Mid-infrared subwavelength modulator based on grating-assisted coupling of a hybrid plasmonic waveguide mode to a graphene plasmon.

This work reports a mid-infrared modulator based on a hybrid plasmonic waveguide with graphene on a grating in its slot region. The modulator utilizes a graphene plasmon for electro-optic tuning in a more practical and effective way than graphene-plasmon-based waveguide devices studied up to now. The hybrid plasmonic waveguide can be easily and efficiently integrated with input and output photonic waveguides. It supports a hybrid plasmonic waveguide mode and a graphene-plasmon-based waveguide mode. Grating-assisted coupling of the former to the latter in it is demonstrated to work successfully even though the two modes have significantly different propagation constants and losses. Theoretical investigation of the modulator shows that the coupling via the grating of length 5.92 µm generates a deep rejection band at a wavelength of 8.014 µm in the transmission spectrum of the output photonic waveguide of the modulator. With the graphene chemical potential tuned between 0.6 eV and 0.65 eV, the transmission at the wavelength is modulated between -27 dB and -1.8 dB. The subwavelength modulator, which may have a large bandwidth and small energy consumption, is expected to play a key role in free-space communications and sensing requiring mid-infrared integrated photonics.

Tip-loaded dissolving microneedles for transdermal delivery of donepezil hydrochloride for treatment of Alzheimer's disease.

Donepezil hydrochloride (DPH) is often used in the treatment of Alzheimer's disease. A new treatment method was developed by encapsulating high DPH content in the tips of dissolving microneedles for rapid, transdermal delivery of a predetermined dose of DPH. The microneedles were prepared by a micromolding method using a hydroxy-propyl-methyl-cellulose (HPMC)-ethanol/water mixture (80:20, v/v) for the tips and carboxy-methyl cellulose (CMC)-water for the base of the needles. The micromolding method involved centrifuging a DPH-HPMC-ethanol/water mixture at 10°C to obtain tips with sufficient mechanical strength. To test their mechanical strength, microneedles with different DPH content were inserted into porcine skin. Then the amount of DPH encapsulated in the microneedles was measured using high-performance liquid chromatography. The efficiency of administering DPH tip-loaded microneedles was investigated using four administrations of a pharmacokinetic test: (1) two oral administration groups (283µg/kg and 692µg/kg) and (2) two microneedle administration groups (283µg/kg and 692µg/kg). High DPH content (up to 78%, w/w) was encapsulated in the microneedle tips without serious loss of mechanical strength by using a mixture of hydroxy-propyl-methyl-cellulose (HPMC) and ethanol/water mixture (80:20, v/v). Because of the distribution of DPH in the tips, 95% of the DPH was delivered into porcine skin after 5min of insertion. As measured by Cmax and AUC, transdermal delivery of DPH tip-loaded microneedles was more effective compared to oral administration of the same dose of DPH. Transdermal delivery could replace oral administration of DPH.

Plasmofluidic Disk Resonators.

Waveguide-coupled silicon ring or disk resonators have been used for optical signal processing and sensing. Large-scale integration of optical devices demands continuous reduction in their footprints, and ultimately they need to be replaced by silicon-based plasmonic resonators. However, few waveguide-coupled silicon-based plasmonic resonators have been realized until now. Moreover, fluid cannot interact effectively with them since their resonance modes are strongly confined in solid regions. To solve this problem, this paper reports realized plasmofluidic disk resonators (PDRs). The PDR consists of a submicrometer radius silicon disk and metal laterally surrounding the disk with a 30-nm-wide channel in between. The channel is filled with fluid, and the resonance mode of the PDR is strongly confined in the fluid. The PDR coupled to a metal-insulator-silicon-insulator-metal waveguide is implemented by using standard complementary metal oxide semiconductor technology. If the refractive index of the fluid increases by 0.141, the transmission spectrum of the waveguide coupled to the PDR of radius 0.9 µm red-shifts by 30 nm. The PDR can be used as a refractive index sensor requiring a very small amount of analyte. Plus, the PDR filled with liquid crystal may be an ultracompact intensity modulator which is effectively controlled by small driving voltage.

Greater trochanteric pain syndrome due to tumoral calcinosis in a patient with chronic kidney disease.

Tumoral calcinosis is a rare syndrome characterized by massive subcutaneous soft tissue deposits of calcium phosphate near the large joints. It is more prevalent in patients with chronic kidney disease undergoing dialysis. A 57-year-old woman was referred to our pain clinic with the complaint of severe pain in the left buttock and lateral hip. The patient had been suffering from chronic kidney disease for 10 years and had been undergoing peritoneal dialysis over the past 5 years. The patient's symptom was initially suspected to be of lumbar origin at the L5 level and a left L5 transforaminal epidural block was performed, but without success. Re-evaluation of the physical examination revealed severe tenderness over the left greater trochanter and piriformis muscle. On ultrasonographic evaluation, multiple mass-like lesions in the left buttock were observed. About 30 mL of fluid was aspirated from the cystic lesions, followed by 30 mL mixture of 0.08% levobupivacaine and triamcinolone 40 mg injected into the bursa under ultrasound guidance, which brought pain relief. Trochanteric bursitis was thought of as the cause of the symptoms. The patient was diagnosed with tumoral calcinosis based on the past medical history, simple plain radiographs, and hip magnetic resonance imaging (MRI). We diagnosed a case of greater trochanteric pain syndrome due to tumoral calcinosis related to chronic kidney disease in a patient whose symptoms had initially been considered to be radiating leg pain caused by lumbar spinal disease. We report our experience of symptomatic improvement following the repeated ultrasound-guided aspiration of calcific fluid and the injection of a mixture of local anesthetic and steroid.

One step hydrothermal synthesis of a carbon nanotube/cerium oxide nanocomposite and its electrochemical properties.

A carbon nanotube (CNT)/cerium oxide composite was prepared by a one-pot hydrothermal reaction in the presence of KOH and capping agent polyvinylpyrrolidone. The nanocomposite displayed pronounced capacitive behaviour with very small diffusion resistance. The electrochemical performance of the composite electrode in a symmetric supercapacitor displayed a high energy density of 35.9 Wh kg(-1) corresponding to a specific capacitance of 289 F g(-1). These composite electrodes also demonstrated a long cycle life with better capacity retention.