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Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator that plays an important role in many signaling pathways, especially those associated with insulin resistance. In this study, we investigated the anti-diabetic potential of 12 natural tanshinones isolated from Salvia miltiorrhiza (S. miltiorrhiza) Bunge (Lamiaceae), deoxyneocryptotanshinone (1), grandifolia F (2), ferruginol (3), cryptotanshinone (4), tanshinone IIA (5), tanshinol B (6), tanshinone IIB (7), tanshinonal (8), methyl tanshinonate (9), 15,16-dihydrotanshinone I (10), tanshinone I (11), and dehydrodanshenol A (12) and evaluated their inhibitory activity against PTP1B. Tanshinones 4, 6 and 12 exhibited potent PTP1B inhibitory activity with IC50 values of 5.5 ± 0.9, 4.7 ± 0.4 and 8.5 ± 0.5 μM, respectively. In addition, tanshinones 1–3, 5 and 7–11 showed promising dose-dependent inhibition of PTP1B over IC50 values ranging from 18.6 to 254.8 μM. Enzyme kinetic analysis of PTP1B inhibition revealed that 4 and 6 were mixed -noncompetitive type inhibitors, whereas 12 was a classical-noncompetitive type inhibitor. Furthermore, 4, 6 and 12 were docked with the PTP1B enzyme using molecular docking simulations (AutoDock 4.2) and exhibited negative binding energy (−6.4 to −8.7 kcal/mol), indicating high binding affinity to PTP1B active site residues. Structure-activity relationships (SAR) analysis revealed that structural modifications of ring A and furan or dihydrofuran ring D on the basic structure of tanshinones influenced their activity. Overall, results indicated that tanshinones from S. miltiorrhiza are potential anti-diabetic candidates that should be explored in the development of preventive and therapeutic modalities for the treatment of diabetes as well as diabetes-associated complications.

In this paper, we focus on the detection of the semantic and structural modifications in documents. We define the following six inter-document relations that we use to represent document modification: Eliminate, Extend, Merge, Split, Rewrite, and Reorder. We also develop a detection model based on a deep neural network to identify the relations between two given documents. We assumed that several modifications can be applied to a document; in this situation, the modifications can overlap each other, so it can be very difficult to detect the applied modifications. We represent a document pair by using a sentence-based similarity matrix, and the inter-document relations are then detected by applying the deep neural network to the similarity matrix. The experiments show that our model performed impressively in the detection of document modifications.

Background Hantavirus infection occurs through the inhalation of aerosolized excreta, including urine, feces, and saliva of infected rodents. The presence of Hantaan virus (HTNV) RNA or infectious particles in urine specimens of patient with hemorrhagic fever with renal syndrome (HFRS) remains to be investigated. Methodology/Principal findings We collected four urine and serum specimens of Republic of Korea Army (ROKA) patients with HFRS. We performed multiplex PCR-based next-generation sequencing (NGS) to obtain the genome sequences of clinical HTNV in urine specimens containing ultra-low amounts of viral genomes. The epidemiological and phylogenetic analyses of HTNV demonstrated geographically homogenous clustering with those in Apodemus agrarius captured in highly endemic areas, indicating that phylogeographic tracing of HTNV genomes reveals the potential infection sites of patients with HFRS. Genetic exchange analyses showed a genetic configuration compatible with HTNV L segment exchange in nature. Conclusion/Significance Our results suggest that whole or partial genome sequences of HTNV from the urine enabled to track the putative infection sites of patients with HFRS by phylogeographically linking to the zoonotic HTNV from the reservoir host captured at endemic regions. This report raises awareness among physicians for the presence of HTNV in the urine of patients with HFRS., Author summary Hantavirus transmission to humans occurs via inhalation of aerosolized excreta, including urine, feces, and saliva of infected rodents. Currently, no report for the etiological evidence associated with urinary Hantaan virus (HTNV) from patients with hemorrhagic fever with renal syndrome (HFRS) is available. Here, we conducted multiplex PCR-based next-generation sequencing (NGS) using urine and serum specimens from four Republic of Korea Army (ROKA) patients with HFRS. The epidemiological and phylogenetic analyses using whole or partial genome sequences of HTNV from urine and serum demonstrated homogenous genetic clustering with HTNV from clinical specimens, circulating at highly endemic sites of patient infection. Among the sequences from ROKA patients, the genomic configuration of ROKA16-10 demonstrated occurrences of the genetic reassortment. Our results suggest that whole or partial genome sequences of HTNV from the urine enabled to track the putative infection sites of patients with HFRS by phylogeographically linking to the zoonotic HTNV from the reservoir host captured at endemic regions. This result provides new insights into presence of HTNV in the urine of patients with HFRS among physicians.

An undescribed 1,3-diphenylpropane derivative, kazinol V and six undescribed prenylated flavonoids, broussonols F–H and broussonols K–M were isolated from the roots of Broussonetia kazinoki Siebold, together with 12 known compounds. This is the first report of the isolation and structure determination of broussonol I from a natural source. The chemical structure of the undescribed compounds was determined using conventional NMR and HRMS data. Absolute configurations were assigned using time-dependent density functional theory calculations and Electronic Circular Dichroism (ECD) spectroscopy. The isolated compounds were screened for their effects on RANKL-induced osteoclast formation using RAW264.7 cells. Among them, broussonols F, G, and K showed strong, dose-dependent antiosteoclastogenic activities. Broussonol K exhibited the most potent inhibitory activity and possessed bone resorption suppressive activity.

Graphical abstract, In this study, chemical investigation of methanol extract of the air-dried fruits of Luffa cylindrica led to the identification of a new δ‐valerolactone (1), along with sixteen known compounds (2–17). Their chemical structures including the absolute configuration were elucidated by extensive spectroscopic analysis and electronic circular dichroism analysis, as well as by comparison with those reported in the literature. For the first time in literature, we have examined the binding potential of the isolated compounds to highly conserved protein, Mpro of SARS-CoV-2 using the molecular docking technique. We found that the isolated saponins (14–17) bind to the substrate‐binding pocket of SARS-CoV-2 Mpro with docking energy scores of –7.13, –7.29, –7.47, and –7.54 kcal.mol–1, respectively, along with binding abilities equivalent to an already claimed N3 protease inhibitor (–7.51 kcal.mol–1).

Background Various size and shape of region of interest (ROI) can be applied for shear-wave elastography (SWE). Purpose To investigate the diagnostic performance of SWE according to ROI settings for breast masses. Material and Methods To measure elasticity for 142 lesions, ROIs were set as follows: circular ROIs 1 mm (ROI-1), 2 mm (ROI-2), and 3 mm (ROI-3) in diameter placed over the stiffest part of the mass; freehand ROIs drawn by tracing the border of mass (ROI-M) and the area of peritumoral increased stiffness (ROI-MR); and circular ROIs placed within the mass (ROI-C) and to encompass the area of peritumoral increased stiffness (ROI-CR). Mean (Emean), maximum (Emax), and standard deviation (ESD) of elasticity values and their areas under the receiver operating characteristic (ROC) curve (AUCs) for diagnostic performance were compared. Results Means of Emean and ESD significantly differed between ROI-1, ROI-2, and ROI-3 ( P max did not ( P = 0.50). For ESD, ROI-1 (0.874) showed a lower AUC than ROI-2 (0.964) and ROI-3 (0.975) ( P SD was significantly different between ROI-M and ROI-MR and between ROI-C and ROI-CR ( P SD in ROI-M and ROI-C were significantly lower than in ROI-MR ( P = 0.041 and 0.015) and ROI-CR ( P = 0.007 and 0.004). Conclusion Shear-wave elasticity values and their diagnostic performance vary based on ROI settings and elasticity indices. Emax is recommended for the ROIs over the stiffest part of mass and an ROI encompassing the peritumoral area of increased stiffness is recommended for elastic heterogeneity of mass.

A previously undescribed nor-dammarane, 3β,20,23-trihydroxy-24,25,26,27-tetranordammarane; three previously undescribed secoiridoid glycosides, ligujaponosides A-B, and iso-oleonuzhenide; and twenty three known compounds, were isolated from the fruits of Ligustrum japonicum Thunb. Their chemical structures were elucidated by extensive spectroscopic analyses, including 1D and 2D NMR, and HRMS. The isolated compounds were screened for immunosuppressive effects on T activated cells by evaluating interleukin-2 (IL-2) production. Among them, sesamin inhibited IL-2 production in Jurkat T cells with an IC50 value of 38 ± 2 μM. In addition, sesamin inhibited the phosphorylation of extracellular signal-regulated protein kinase (ERK), a member of the mitogen-activated protein kinase (MAPK) family, in phorbol 12-myristate 13-acetate (PMA)/A23187-stimulated T cells. Therefore, sesamin was demonstrated to inhibit T cell activation via regulation of MAPK phosphorylation pathway.

Two new phloroglucinols (7 and 10), along with 12 known derivatives (1-6, 8-9, and 11-14), were isolated from the roots of Dryopteris crassirhizoma (Aspiadaceae). Their chemical structures were elucidated by various spectroscopic methods (1H NMR, 13C NMR, COSY, HMQC, and HMBC) and high-resolution mass spectrometry. All isolates (1-14) were tested for their inhibitory effects on melanin production in B16F10 murine melanoma cells. Norflavaspidic acid AB (8), norflavaspidic acid PB (9), and flavaspidic acid PB (12) inhibited melanin production with IC50 values of 181.3, 35.7, and 38.9 μM, respectively. Compound 9 was also shown to inhibit tyrosinase activity in a dose-dependent manner and melanogenesis with an IC50 value of 5.9 μM in B16F10 cells stimulated with 3-isobutyl-1-methylxanthine (IBMX).

GPR40 is one of the most prominent targets for the treatment of type 2 diabetes (T2DM), and has its role in insulin secretion via blood-glucose-dependent manner with a minimum risk of hypoglycemia. In order to discover novel antidiabetics bearing these benefits, we screened various derivatives with two distinct pharmacophores. Both series displayed potent agonistic activities for GPR40 in vitro functional assay. Through additional ADME and in vivo efficacy evaluations, we identified the potent hit candidate 2j as a novel GPR40 agonist.

Human embryonic stem cells (hESCs) possess unique properties in terms of self-renewal and differentiation, which make them particularly well-suited for use in tissue engineering and regenerative medicine. The differentiation of hESCs in the form of human embryoid bodies (hEBs) recapitulates early embryonic development, and hEBs may provide useful insight into the embryological development of humans. Herein, cell-penetrating magnetic nanoparticles (MNPs) were utilized to form hEBs with defined sizes and the differentiation patterns were analyzed. Through intracellular delivery of MNPs into the hESCs, suspended and magnetized hESCs efficiently clustered in to hEBs driven by magnetic pin-based external magnetic forces. The hEB size was controlled by varying the suspended cell numbers that were applied in the magnetic pin system. After 3 days of differentiation in a suspended condition, ectodermal differentiation was observed to have been enhanced in the small hEBs (150 μm in diameter) while endodermal and mesodermal differentiation were enhanced in large hEBs (600 μm in diameter). This indicates that the size of the hEBs plays an important role in the early lineage commitment of hESCs, and MNP-based control of the hEB size would be a novel, useful methodology for lineage-specific hESC differentiation.

Five new compounds, 10-oxomornigrol F (1), (7″R)-(-)-6-(7″-hydroxy-3″,8″-dimethyl-2″,8″-octadien-1″-yl)apigenin (2), ramumorin A (3), ramumorin B (4), and (4S,7S,8R)-trihydroxyoctadeca-5Z-enoic acid (5), together with 31 known compounds (6-36), were isolated from the twigs of Morus alba (Moraceae). The chemical structures of these compounds were established using spectroscopic analyses, 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and Mosher's methods. The anti-inflammatory activities of the compounds were evaluated by investigating their ability to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophage RAW 264.7 cells. Compounds 1, 2, 13, 17, 19, 25-28, and 32 showed inhibitory effects with IC50 values ranging from 2.2 to 5.3μg/mL. Compounds 1, 2, 17, 25, and 32 reduced LPS-induced inducible nitric oxide synthase (iNOS) expression in a concentration-dependent manner. In addition, pretreating the cells with compound 1, 17, and 32 significantly suppressed LPS-induced expression of cyclooxygenase-2 (COX-2) protein.

A phytochemical investigation into the bark of Erythrophleum fordii yielded four new compounds, two new cassaine diterpenoids (erythrofordin T and U, 1 and 2) and two new cassaine diterpenoid amines (erythroformine A and B, 6 and 7), as well as nine known compounds. We report for the first time the isolation of erythrofordin V (3) from a natural source and that of the remaining eight known diterpenoids (4-5, 8-13) from E. fordii. All structures were elucidated using spectroscopic analysis. Cytotoxic activity of the isolated compounds (1-13) was examined in vitro against three non-small cell lung cancer cell lines (A549, NCI-H1975, and NCI-H1229) using the MTT assay. Cassaine diterpene amines (6-10, 12, 13) exhibited potent cytotoxic activity against all three cell lines with IC50 values between 0.4μM and 5.9μM. Erythroformine B (7) significantly induced apoptosis in all three cancer cells in a concentration-dependent manner.

In the present study, ten alkaloids, namely chabamide (1), pellitorine (2), retrofractamide A (3), pyrroperine (4), isopiperolein B (5), piperamide C9:1 (8E) (6), 6,7­dehydrobrachyamide B (7), 4,5-dihydropiperine (8), dehydropipernonaline (9), and piperine (10), were isolated from the fruits of Piper nigrum. Among these, chabamide (1), pellitorine (2), retrofractamide A (3), isopiperolein B (5), and 6,7­dehydrobrachyamide B (7) exhibited significant inhibitory activity on lipopolysaccharide-induced nitric oxide (NO) production in RAW264.7 cells, with IC50 values of 6.8, 14.5, 30.2, 23.7, and 38.5 μM, respectively. Furthermore, compound 1 inhibited lipopolysaccharide-induced NO production in bone marrow-derived macrophages with IC50 value of 9.5 μM. Consistent with NO inhibition, treatment of RAW264.7 cells with chabamide (1), pellitorine (2), and 6,7­dehydrobrachyamide B (7) suppressed expression of inducible NO synthase and cyclooxygenase-2. Chabamide (1), pellitorine (2), and 6,7­dehydrobrachyamide B (7) induced heme-oxygenase-1 expression at the transcriptional level. In addition, compound 1 induced the nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) and upregulated the expression of Nrf2 target genes, NAD(P)H:quinone oxidoreductase 1 and γ-glutamyl cysteine synthetase catalytic subunit, in a concentration-dependent manner in RAW264.7 cells. These findings suggest that chabamide (1) from P. nigrum exert antiinflammatory effects via the activation of the Nrf2/heme-oxygenase-1 pathway; hence, it might be a promising candidate for the treatment of inflammatory diseases. Copyright © 2017 John Wiley & Sons, Ltd.

This study was designed to assess the outcomes of subcentimeter thyroid nodules with highly suspicious ultrasonography (US) features and to investigate the predictive factors associated with malignancy and aggressive biological behavior to determine appropriate candidate factors for active surveillance. Between June 2011 and December 2013, 1866 subcentimeter thyroid nodules with highly suspicious US features that were subjected to US-guided fine needle aspiration and subsequent surgery or US follow-up of at least 2 years were evaluated. A multivariate logistic regression analysis was performed to identify independent clinical characteristics and US features associated with the malignancy rate and aggressive biological behavior. Of the 1866 subcentimeter thyroid nodules, 821 (44.0%) were benign and 1045 (56.0%) were malignant. Age younger than 45 years, presence of microcalcification, and a taller than wide shape on US were associated independently with malignancy in the subcentimeter thyroid nodules (P

The proprietary DA-5512 formulation comprises six herbal extracts from traditional oriental plants historically associated with therapeutic and other applications related to hair. Here, we investigated the effects of DA-5512 on the proliferation of human dermal papilla cells (hDPCs) in vitro and on hair growth in C57BL/6 mice and conducted a clinical study to evaluate the efficacy and safety of DA-5512. DA-5512 significantly enhanced the viability of hDPCs in a dose-dependent manner (p<0.05), and 100 ppm of DA-5512 and 1 μM minoxidil (MXD) significantly increased the number of Ki-67-positive cells, compared with the control group (p<0.05). MXD (3%) and DA-5512 (1%, 5%) significantly stimulated hair growth and increased the number and length of hair follicles (HFs) versus the controls (each p<0.05). The groups treated with DA-5512 exhibited hair growth comparable to that induced by MXD. In clinical study, we detected a statistically significant increase in the efficacy of DA-5512 after 16 weeks compared with the groups treated with placebo or 3% MXD (p<0.05). In conclusion, DA-5512 might promote hair growth and enhance hair health and can therefore be considered an effective option for treating hair loss.

본 논문은 간호학생들의 자기 주도 학습에 대한 인식수준과 수행수준을 파악하기 위하여 시도되었다. 각종 자기주도 학습과 관련 문헌을 고찰하여 자기 주도 학습의 핵심개념을 규명한 다음 이에 부합되는 루브릭을 개발하였다. 이를 간호 대학생에게 적용하여 자기 주도 학습에 대한 인식수준과 실행수준을 확인하였다. 연구결과에 의하면 간호학생들의 자기 주도 학습에 대한 인식수준과 수행수준은 모든 항목에서 유의한 차이가 있었다. 또한 간호학생들의 자기 주도 학습에 대한 수행수준은 입시성적에 따라 간호학을 선택한 학생이 낮았지만, 학년에 따른 유의한 차이가 없었다. 자기 주도 학습에 대한 인식수준은 전공만족도별, 학업성취도별, 전공 선택 동기 별로 유의한 차이가 없었다. 결론적으로 간호대학생의 자기주도 학습에 대한 인식수준과 수행수준은 일치하지 않았으며, 이는 학생들이 자기 주도 학습의 필요성은 충분히 인식하고 있지만 실제로 실행에 옮기고 있지 않고 있음을 의미한다. 이에 간호육자들은 교육대상 학생들의 자기 주도 학습 능력과 현황을 구체적으로 파악하고 이를 강화하고 향상시킬 수 있는 교수학습 전략을 개발해야 할 필요성이 있다.

To Software product line (SPL) engineering process be efficient, integrated environment supporting SPL is necessary. So far, domain engineering process supporting tools or specific purpose tools such as variability management, feature modeling have been suggested. In this paper, we suggested SW Visualization tools as application engineering supporting tools and VULCAN workbench as domain engineering supporting tools. And we suggested integration mechanism between well-defined open source software tools.

Hantaan virus (HTNV), identified in the striped field mouse (Apodemus agrarius), belongs to the genus Hantavirus of the family Bunyaviridae and contains tripartite RNA genomes, small (S), medium (M), and large (L) segments. HTNV is a major causative for hemorrhagic fever with renal syndrome (HFRS) with fatality rates ranging from 1% to 15% in the Republic of Korea (ROK) and China. Defining of HTNV whole-genome sequences and isolation of the infectious particle play a critical role in the characterization and preventive and therapeutic strategies of hantavirus outbreaks. Next-generation sequencing (NGS) provides an advanced tool for massive genomic sequencing of viruses. However, the isolation of viral infectious particles is a huge obstacle to investigate and develop anti-virals for hantaviruses. Here, we report 12 HTNV isolates from lung tissues of the striped field mouse in the highly HFRS-endemic areas. Sequence-independent, single-primer amplification (SISPA) NGS was attempted to recover the genomic sequences of HTNV isolates. The nucleotide sequence of HTNV S, M, and L segments were covered up to 99.4–100%, 97.5–100%, and 95.6–99.8%, respectively, based on the full length of the prototype HTNV 76-118. The whole-genome sequencing of HTNV isolates was accomplished by additional reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification cDNA ends (RACE) PCR. In conclusion, this study will lead to the attempt and usage of SISPA NGS technologies to delineate the whole-genome sequence of hantaviruses, providing a new era of viral genomics for the surveillance, trace, and disease risk management of HFRS incidents.

It is not easy to define the well-defined process for software research project but it is important to keep the tracking the progress of the projects. Without the process, it is not easy to measure the progress since we cannot define the unit of measure. In this paper we suggested RD(research descriptor) concept to define the unit of measure. Also we suggested RD relation to trace the progress the research workflow. With suggested mechanism, we can monitor the research project process and visualization the progress.

Harmful materials in the blood are prevented from entering the healthy brain by a highly selective blood–brain barrier (BBB), and impairment of barrier function has been associated with a variety of neurological diseases. In Alzheimer's disease (AD), BBB breakdown has been shown to occur even before cognitive decline and brain pathology. To investigate the role of the cerebral vasculature in AD, a physiologically relevant 3D human neural cell culture microfluidic model is developed having a brain endothelial cell monolayer with a BBB‐like phenotype. This model is shown to recapitulate several key aspects of BBB dysfunction observed in AD patients: increased BBB permeability, decreased expression of claudin‐1, claudin‐5, and VE‐cadherin, increased expression of matrix‐metalloproteinase‐2 and reactive oxygen species, and deposition of β‐amyloid (Aβ) peptides at the vascular endothelium. Thus, it provides a well‐controlled platform for investigating BBB function as well as for screening of new drugs that need to pass the BBB to gain access to neural tissues., An increase in permeability of the blood–brain barrier (BBB) has long been considered a key factor in the cause and consequences of Alzheimer's disease (AD). In this study, a physiologically relevant 3D model is developed and used to investigate several key aspects of BBB dysfunction in AD and to provide a standardized platform for screening of new drugs.

To investigate whether monitoring with ultrasound and MR imaging before, during and after neoadjuvant chemotherapy (NAC) can predict axillary response in breast cancer patients. A total of 131 breast cancer patients with clinically positive axillary lymph node (LN) who underwent NAC and subsequent surgery were enrolled. They had ultrasound and 3.0 T-MR examinations before, during and after NAC. After reviewing ultrasound and MR images, axillary LN features and tumour size (T size) were noted. According to LN status after surgery, imaging features and their diagnostic performances were analysed. Of the 131 patients, 60 (45.8%) had positive LNs after surgery. Pre-NAC T size at ultrasound and MR was different in positive LN status after surgery (p

Four new diterpene-type compounds normiltirone (

Development of antagonistic antibody (Ab) against interleukin-4 receptor alpha (IL-4Rα) subunit of IL-4/IL-13 receptors is a promising therapeutic strategy for T helper 2 (TH2)-mediated allergic diseases such as asthma and atopic dermatitis. Here we isolated anti-human IL-4Rα antagonistic Abs from a large yeast surface-displayed human Ab library and further engineered their complementarity-determining regions to improve the affinity using yeast display technology, finally generating a candidate Ab, 4R34.1.19. When reformatted as human IgG1 form, 4R34.1.19 specifically bound to IL-4Rα with a high affinity (KD ≈ 178 pM) and effectively blocked IL-4- and IL-13-dependent signaling in a reporter cell system at a comparable level to that of the clinically approved anti-IL-4Rα dupilumab Ab analogue. Epitope mapping by alanine scanning mutagenesis revealed that 4R34.1.19 mainly bound to IL-4 binding sites on IL-4Rα with different epitopes from those of dupilumab analogue. Further, 4R34.1.19 efficiently inhibited IL-4-dependent proliferation of T cells among human peripheral blood mononuclear cells and suppressed the differentiation of naïve CD4+ T cells from healthy donors and asthmatic patients into TH2 cells, the activities of which were comparable to those of dupilumab analogue. Our work demonstrates that both affinity and epitope are critical factors for the efficacy of anti-IL-4Rα antagonistic Abs.

Regulatory T cells (Treg) are targeted for cancer immunotherapy because they suppress antitumor immunity. Although the importance of neuropilin-1 (NRP1) in the stability and function of intratumoral Tregs is well-documented, targeting of NRP1+ Tregs for anticancer immunotherapy has not been well explored. Here, we found that an NRP1 antagonist [Fc(AAG)-TPP11], generated by fusion of the NRP1-specific binding peptide TPP11 with the C-terminus of an effector function–deficient immunoglobulin Fc(AAG) variant, inhibits intratumoral NRP1+ Treg function and stability. Fc(AAG)-TPP11 triggered the internalization of NRP1, reducing its surface expression on Tregs and thereby inhibiting the suppressive function of Tregs. In two murine syngeneic tumor models, Fc(AAG)-TPP11 retarded tumor growth, comparable with a Treg-depleting anti–CTLA-4 antibody, without noticeable toxicity. Fc(AAG)-TPP11 inhibited NRP1-dependent Treg function, inducing unstable intratumoral Tregs, with reduced expression of Foxp3 and enhanced production of IFNγ, which subsequently increased the functionality and frequency of intratumoral CD8+ T cells. We also observed selective expression of NRP1 on Tregs isolated from human tumors, but not from the blood of healthy donors and patients with cancer, as well as ex vivo inhibition of intratumoral NRP1+ Treg function by Fc(AAG)-TPP11. Our results suggest that the NRP1 antagonist Fc(AAG)-TPP11 has therapeutic potential for the inhibition of intratumoral NRP1+ Tregs with limited unfavorable effects on peripheral Tregs.

Purpose To evaluate the long-term incidence and risk of glaucoma after bilateral congenital cataract surgery in microphthalmic eyes. Design Retrospective, observational case series. Methods Subjects : Children with microphthalmic eyes who had undergone surgery for bilateral congenital cataract within 6 months of birth and been followed up for at least 5 years. Procedures : Review of medical records at our institution. Main Outcome Measures : Probability of an eye's developing glaucoma after bilateral congenital cataract surgery and associated risk factors. Results Thirty-eight eyes of 19 children with bilateral congenital cataract were included. The mean age at surgery was 3.2 ± 1.7 months, and the mean follow-up duration was 7.79 ± 2.61 years. After cataract surgery, 11 eyes (29.0%) developed glaucoma at the age of 4.0 ± 1.4 years. Three of these eyes underwent Ahmed glaucoma valve implantation surgery. The probability of an eye's developing glaucoma was estimated to be 32.0% by 10 years after surgery. In a multivariate analysis, axial length was significantly associated with glaucoma development (odds ratio = 0.364, P = .025). Age at the time of cataract surgery, corneal diameter, and aphakia did not affect the risk of glaucoma (P > .10). Eyes without glaucoma had a better final visual outcome than those with glaucoma (0.75 ± 0.60 and 1.47 ± 1.10 logMAR, respectively, P = .049). Conclusions The long-term cumulative risk of postoperative glaucoma development was 32.0% by 10 years after bilateral congenital cataract surgery. Because the risk of developing glaucoma persists for several years after surgery, careful monitoring and control of intraocular pressure is needed to preserve vision in such patients.

Bisphenol A [BPA, 2,2-bis-(4-hydroxyphenyl)propane] is one of the most prevalent synthetic environmental estrogens; as an endocrine disruptor, it is associated with endocrine-related cancers including breast, ovarian, and prostate. However, the mechanisms by which BPA contributes to carcinogenesis are unclear. This study aims to clarify its toxic effects on mitotic cells and investigate the molecular mechanism. In vitro effects of BPA on mitotic progression were examined by performing experiments on HeLa cells. Proteins involved in mitotic processes were detected by Western blot, live cell imaging, and immunofluorescence staining. The results showed that BPA increased chromosomal instability by perturbing mitotic processes such as bipolar spindle formation and spindle microtubule attachment to the kinetochore. BPA prolonged mitotic progression by disturbing spindle attachment and concomitant activating spindle assembly checkpoint (SAC). Mechanistically, BPA interfered proper localization of HURP to the proximal ends of spindle microtubules, Kif2a to the minus ends of spindle microtubules, and TPX2 on the mitotic spindle. This mislocalization of microtubule associated proteins (MAPs) is postulated to lead to spindle attachment failure. Furthermore, BPA caused multipolar spindle by inducing centriole overduplication and premature disengagement. Although BPA acts as an estrogen receptor (ER) agonist, mitotic defects caused by BPA occurred in an ER-independent manner. Our findings indicate that BPA may stimulate carcinogenesis not only by acting as an endocrine disruptor but also by increasing chromosomal instability during mitosis.

Four new diterpene-type compounds normiltirone (3) and isosalviamides F-H (14–16) together with twelve known compounds (1, 2, 4–13) were isolated from the roots of Salvia miltiorrhiza. Their structures were mainly elucidated from detailed spectroscopic data. All isolated compounds were evaluated for their ability to inhibit lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophages. Compound 11 showed a strong inhibitory effect, with an IC50 value of 3.4 ± 1.2 μM.

Supplemental material, JOH893036 Supplemental Material3 for “Thank You for Listening”: An Exploratory Study Regarding the Lived Experience and Perception of Medical Errors Among Those Who Receive Care by Daniel Terry, Jeong-ah Kim, Julia Gilbert, Sunny Jang and Hoang Nguyen in International Journal of Health Services

The area of mobile healthcare (mHealth) is expected to expand from disease treatment to various areas, such as disease prevention, telemedicine, and universal health promotion. Under such vertical and horizontal medical industry expansion, the mHealth concept for the improvement of the quality of medical services, such as telemedicine and medical record automation, will become the keyword of the industry while mobile devices and networks will be advanced. In this paper, architecture of mHealth is suggested for multi-product, small-quantity production and a majority constitution by small manufacturers.

Product Line Architecture design is a key activity for developing successful Software Product Line projects. But it is difficult and complex task since architecture of software product line should be considered with variability. In this research, we addressed detail guidelines for identifying the component of architecture from the feature model and defining the variability of component in concerns of feature.

This paper proposes an approach to carrying out context data preprocessing gathered from smartphone users to support context-aware authentication. Context-aware authentication is a technique to implicitly authenticate a smartphone user using contextual data (e.g., call log, location) without explicitly requesting the user’s any actions. In order to enable context-aware authentication, a user’s contextual data should be carefully processed for learning user’s past contextual patterns in consideration of user’s hourly, daily, weekly or monthly behaviors. In this paper, we gathered contextual data from 200 voluntary smartphone users for about 2 years and showed what the appropriate contextual data is preprocessing for performing context-aware authentication.

The author would like to include conflict of interest statement of the online published article. The correct conflict of interest statement should read as.

Software development companies are trying to produce their software products by development processes. However, software development companies have a difficulty on applying a development process to various software development domains. The difficulty like this happens because process tailoring is not a simple work. Process tailoring needs various experiences and involves an intimate knowledge of several aspects of software engineering, but there is a limit in improving the quality of software development processes which a process engineer defines with heuristic way by relying on experience or knowledge of the individual. To ameliorate these problems, we proposed a variability analysis method with cases applying domain analysis technique on software product line to make it possible to reduce the dependency on knowledge or experience of a process engineer in the software development company for process tailoring. If a process engineer tries to apply a suggested method for process tailoring in the software development company, a process engineer can obtain reusable process assets through identifying variabilities in existing process assets.

A cancer pain clinic (CPC) service is a thorough, comprehensive consultation service for patients with uncontrolled cancer pain. The aim of this study was to determine the success of a new CPC service with enrollment via electronic health record-based automatic screening at 1 cancer center in Korea.A case-control study and a satisfaction survey.The intervention group (n = 158) was enrolled in the CPC service, whereas the control group (n = 158), which was matched using propensity scores, did not participate in the service. The pain scores of participants were compared using an independent t test. Thirty-nine patients and 20 physicians completed a self-administered survey on instructions for pain-relief medications, effective usage of long-acting and short-acting opioids, perceptions of or barriers to CPC services, knowledge of opioid use, and overall satisfaction.Although the baseline pain score of the intervention group was significantly higher than that of the control group (P = .013), the difference in the decrease of pain between the groups was significant at days 1 (P = .001) and 2 (P = .039). Although the difference in pain scores disappeared on day 3, total pain score was significantly lower in the intervention group than in the control group (P = .012). When comparing pain relief events (4 points on a 0-10 numeric rating scale that measured pain daily), the intervention group experienced more relief events than did controls (P = .017). Patients were satisfied with their physicians giving clear instructions and considering their opinions about pain-relief medications. The oncology residents expressed satisfaction with the management of patients with opioid-naïve or intractable pain.The new CPC service seems to provide effective pain relief and users seem to be highly satisfied with it. These results support the importance of an integrated and specialized approach to cancer-related pain management.

Sixteen compounds, including six flavonoids (1–6), one lignan (7), three megastigmanes (8–10), three triterpenoids (11–13), and three benzoic acid derivatives (14–16) were isolated and structurally elucidated from the pseudo-fruits of Hovenia dulcis. Their structures were analyzed by NMR spectroscopic and data comparison. Among them, compounds 4, 7–11, 13, 15, and 16 were isolated from the Hovenia genus for the first time. The chemotaxonomic significance of the isolates was also described, which revealed a relationship between H. dulcis and H. acerbar as well as other species belonging to the Rhamnaceae family.

This study aimed to investigate whether the elasticity index of shear-wave elastography (SWE) can predict cervical lymph node (LN) metastasis of papillary thyroid carcinoma (PTC). This retrospective study included 363 patients with a surgical diagnosis of PTC who underwent preoperative SWE evaluation. The elasticity indices of PTC (E mean, E max, E min, E ratio-p, and E ratio-m) and gray-scale ultrasound (US) parameters (extrathyroidal extension, multifocality, and cervical LN metastasis) were correlated with the pathologic staging parameters. The optimal cutoff values for the elasticity indices were determined for the prediction of cervical LN metastasis, and diagnostic performance was compared between gray-scale US and the combined application of gray-scale US and SWE. The findings showed E mean and E max to be associated with central LN metastasis (P = 0.037) and E min to be associated with lateral LN metastasis (P = 0.015). An E mean value higher than 124 kPa or an E max value higher than 138 kPa with suspicious gray-scale US findings improved the sensitivity and area under the curve (AUC) for predicting central LN metastasis (sensitivity, 45.4 and 44.6 % vs. 28 %, P

Purpose: The goal of this study was to assess the clinicopathologic and ultrasonographic features of thyroid nodules with nondiagnostic results on repeat ultrasonography (US)-guided fineneedle aspiration biopsy (FNAB) according to size and the number of suspicious findings and to determine the proper management of nodules with consecutive nondiagnostic results. Methods: This retrospective study included 297 nodules with nondiagnostic results on repeat FNAB that were evaluated by US over the course of at least 12 months of follow-up, a follow-up biopsy, or an operation. We compared clinical and US variables between benign and malignant nodules in thyroid nodules with repeat nondiagnostic results. Results: The comparison of benign and malignant nodules with repeat nondiagnostic results revealed that age, marked hypoechogenicity, irregular or microlobulated margins, microcalcifications, and nonparallel shape were significantly associated with malignancy. Multivariate logistic regression analysis in malignant nodules revealed that microcalcifications and irregular or microlobulated margins were independently associated with malignancy. Among them, only irregular or microlobulated margins were independently significant as a predictor of malignancy in repeatedly nondiagnostic nodules measuring >10 mm. Using receiver operating characteristic analysis, the best cutoff value for the “number of suspicious findings” between benign and malignant nodules was three in nodules of all sizes, three in nodules measuring ≤10 mm, and two in nodules measuring >10 mm. Conclusion: Irregular or microlobulated margins may be the most frequent US features in repeatedly nondiagnostic nodules >10 mm. The presence of “two or more suspicious findings” can be used as the cutoff for distinguishing benign and malignant nodules.

Three polyacetylenes, one novel and two known. were isolated from the root of Angelica tenuissima. U ing 1H- and13C_NMR, COSY. HMBC, and HMQC, their truciure were found to be (3R,8S)-heptadeca-1-en-4.6-diyne-3,8-diol (1), falcarindiol (2). and oplopandiol (3). Absolute configuration of compound 1 were established using Mosher`s esterification. In addition. the polyacetylenes (1 - 3) were evaluated for their anti-inflammatory activity. Compounds 1 and 3 showed potent inhibitory activity against lipopolysaccharide-induced nitric oxide (N0) production in RAW267.7 macrophage cell with IC50 value of 4.31 and 5.06 μM. respectively. Compound 1. strongly inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 in a concentration-dependent manner.

Background The purpose of this study was to investigate the role of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) as a prognostic marker in conventional papillary thyroid carcinoma (PTC). Methods A total of 397 patients who underwent ultrasound-guided fine-needle aspiration biopsy (FNAB) and surgery for conventional PTCs were enrolled. The association between the Bethesda category and histopathologic result was evaluated. Results Among the Bethesda categories, a significant difference was found in the presence of extrathyroidal extension (Bethesda category III, 3.2% [7 of 220]; category V, 19.1% [42 of 220]; and category VI, 77.7% [171 of 220]; p < .001) and lymph node metastasis (Bethesda category III, 3.8% [6 of 156]; category V, 16.7% [26 of 156]; and category VI, 79.5% [124 of 156]; p < .001). Multivariate analysis showed that the Bethesda category was independently predictive of extrathyroidal extension (p = .013) and lymph node metastasis (p = .035). Conclusion Conventional PTC with a higher Bethesda category at the time of cytology diagnosis would be poor prognosis. © 2016 Wiley Periodicals, Inc. Head Neck, 2016

Hantaan virus (HTNV), of the family Bunyaviridae, causes hemorrhagic fever with renal syndrome (HFRS) in humans. Although the majority of epidemiologic studies have found that rodents are seropositive for hantavirus-specific immunoglobulin, the discovery of hantavirus RNA in seronegative hosts has led to an investigation of the presence of HTNV RNA in rodents captured in HFRS endemic areas. HTNV RNA was detected in seven (3.8%) of 186 anti-HTNV IgG seronegative rodents in Republic of Korea (ROK) during 2013-2014. RT-qPCR for HTNV RNA revealed dynamic virus-host interactions of HTNV in areas of high endemicity, providing important insights into the epidemiology of hantaviruses.

Complete hydrolysis of κ-carrageenan produces two sugars, D-galactose and 3,6-anhydro-D-galactose (D-AnG). At present, however, we do not know how carrageenan-degrading microorganisms metabolize D-AnG. In this study, we investigated the metabolic pathway of D-AnG degradation by comparative genomic analysis of Cellulophaga lytica LIM-21, Pseudoalteromonas atlantica T6c, and Epulopiscium sp. N.t. morphotype B, which represent the classes Flavobacteria, Gammaproteobacteria, and Clostridia, respectively. In this bioinformatic analysis, we found candidate common genes that were believed to be involved in D-AnG metabolism. We then experimentally confirmed the enzymatic function of each gene product in the D-AnG cluster. In all three microorganisms, D-AnG metabolizing genes were clustered and organized in operon-like arrangements, which we named as the dan operon (3,6-d-anhydro-galactose). Combining bioinformatic analysis and experimental data, we showed that D-AnG is metabolized to pyruvate and D-glyceraldehyde-3-phosphate via four enzyme-catalyzed reactions in the following route: 3,6-anhydro-D-galactose → 3,6-anhydro-D-galactonate → 2-keto-3-deoxy-D-galactonate (D-KDGal) → 2-keto-3-deoxy-6-phospho-D-galactonate → pyruvate + D-glyceraldehyde-3-phosphate. The pathway of D-AnG degradation is composed of two parts: transformation of D-AnG to D-KDGal using two D-AnG specific enzymes and breakdown of D-KDGal to two glycolysis intermediates using two DeLey-Doudoroff pathway enzymes. To our knowledge, this is the first report on the metabolic pathway of D-AnG degradation.