bluuebunny/crossref_metadata_2025 huggingface dataset:
Bladder Transplantation of Amniotic Fluid Stem Cell may Ameliorate Bladder Dysfunction After Focal Cerebral Ischemia in Rat
Authors: Liang Ching-Chung , Shaw S.W. Steven , Huang Yung-Hsin , Lin Yi-Hao , Lee Tsong-Hai
Published: March 2017

The objective is to investigate whether human amniotic fluid stem cells (hAFSCs) grafting into the bladder may influence bladder functional and molecular changes in an animal stroke model. Female rats were divided into three groups: sham, middle cerebral artery occlusion (MCAO) alone, and MCAO plus 1 × 106 hAFSCs transplanting into bladder wall. Bladder function was analyzed by cystometry at days 3 and 10 after MCAO. The expressions of bladder nerve growth factor (NGF), M2-muscarinic, M3-muscarinic, and P2X1 receptors were measured by immunohistochemistry and real-time polymerase chain reaction. When compared with sham-operated group, MCAO alone rats had significant increase in residual volume and decrease in voided volume and intercontraction interval; however, these bladder dysfunctions were improved following hAFSCs transplantation. The immunoreactivities of NGF, M3, and P2X1 significantly decreased at days 3 and 10, but M2 increased at day 3 after MCAO. Following hAFSCs transplantation, the immunoreactivities of NGF and P2X1 significantly increased at day 3, and M2 increased at day 10 after MCAO. The mRNAs of NGF, M2, and M3 significantly increased at day 3, but NGF and M2 decreased at day 10 after MCAO. Following hAFSCs transplantation, there was significant decrease in M2 mRNA at day 3 and increase in P2X1 mRNA at days 3 and 10 after MCAO. Bladder dysfunction caused by MCAO can be improved by hAFSCs transplanting into bladder which may be related to the expressions of bladder NGF, and muscarinic and P2X1 receptors.
Flexible Nonvolatile Transistor Memory with Solution‐Processed Transition Metal Dichalcogenides
Authors: Kim Richard Hahnkee , Lee Jinseong , Kim Kang Lib , Cho Suk Man , Kim Dong Ha , Park Cheolmin
Published: March 2017

Nonvolatile field‐effect transistor (FET) memories containing transition metal dichalcogenide (TMD) nanosheets have been recently developed with great interest by utilizing some of the intriguing photoelectronic properties of TMDs. The TMD nanosheets are, however, employed as semiconducting channels in most of the memories, and only a few works address their function as floating gates. Here, a floating‐gate organic‐FET memory with an all‐in‐one floating‐gate/tunneling layer of the solution‐processed TMD nanosheets is demonstrated. Molybdenum disulfide (MoS2) is efficiently liquid‐exfoliated by amine‐terminated polystyrene with a controlled amount of MoS2 nanosheets in an all‐in‐one floating‐gate/tunneling layer, allowing for systematic investigation of concentration‐dependent charge‐trapping and detrapping properties of MoS2 nanosheets. At an optimized condition, the nonvolatile memory exhibits memory performances with an ON/OFF ratio greater than 104, a program/erase endurance cycle over 400 times, and data retention longer than 7 × 103 s. All‐in‐one floating‐gate/tunneling layers containing molybdenum diselenide and tungsten disulfide are also developed. Furthermore, a mechanically‐flexible TMD memory on a plastic substrate shows a performance comparable with that on a hard substrate, and the memory properties are rarely altered after outer‐bending events over 500 times at the bending radius of 4.0 mm.
Debates in Stuart History
Authors: Hutton Ronald
Published: March 2017

In this essential introduction to the writing of Stuart history, Ronald Hutton provides a clear and authoritative guide to both the current condition of the discipline and its historiography. Hutton helps students to understand some of the key recent debates and shows them how to set their reading in context. He also provides a new sense of why historians of the Stuart period, both collectively and individually, perceive the past in particular ways, and shows how these perceptions alter over time.
Tau and amyloid β proteins distinctively associate to functional network changes in the aging brain
Authors: Sepulcre Jorge , Sabuncu Mert R. , Li Quanzheng , El Fakhri Georges , Sperling Reisa , Johnson Keith A.
Published: March 2017

Introduction

Misfolded tau and amyloid β (Aβ) proteins progressively accumulate in the human brain, causing altered neuronal function and neurodegeneration. This study sought to investigate whether the wide spectrum of functional reorganization in aging brains of cognitively normal individuals relates to specific pathological patterns of tau and Aβ deposits.

Methods

We used functional connectivity neuroimaging and in vivo tau and Aβ positron emission tomography scans to study cortical spatial relationships between imaging modalities.

Results

We found that a negative association between tau and functional connectivity combined with a positive association between Aβ and functional connectivity is the most frequent cortical pattern among elderly subjects. Moreover, we found specific brain areas that interrelate hypoconnectivity and hyperconnectivity regions.

Discussion

Our findings have critical implications to understanding how the two main elements of Alzheimer's disease–related pathology affect the aging brain and how they cause alterations in large‐scale neuronal circuits.
Numerical analysis of heat-curved I-girders
Authors: Gergess Antoine , Sen Rajan
Published: March 2017

Heat curving is a practical and economical process used by steel fabricators for curving structural steel. In this method, the flange edges of a fabricated straight girder are asymmetrically heated to induce residual curvature on cooling. Available analytical methods for predicting the resulting residual stress, strain and curvature are complex and iterative because of the need to account for material and geometric non-linearity. This paper presents a single-step, non-iterative, numerical procedure for determining the effects of heat-curving on residual stress and strain based on a previously developed simplified analysis. Thermal equilibrium equations for idealized heating profiles are first recast in a general parametric form and then solved numerically for standard heating width and temperature using modern technical computing. The resulting solutions are expressed as polynomial functions to allow the solution space for the residual curvature to be graphically represented. Curvature predictions using this simplified approach are shown to be within 11% of measured values and within 5% of values obtained using more rigorous numerical methods.

Highlights The paper presents a simplified computational method for heat curving steel. Equations for non-linear stress distribution are cast in a parametric form and solved numerically using Wolfram Mathematica V.9.0 computer algebra package. Solutions are presented as polynomials and graphical plots to directly calculate the curvature. Legitimacy is confirmed based on comparisons with available experimental and theoretical values.
Associations of VEGF Gene Polymorphisms with Erectile Dysfunction and Related Risk Factors
Authors: Lee Yung-Chin , Huang Shu-Pin , Tsai Chia-Chun , Cheng Kai-Hung , Juan Yung-Shun , Wu Wen-Jeng , Bao Bo-Ying , Huang Chun-Nung , Wang Chii-Jye , Liu Chia-Chu
Published: March 2017

Background

Repeated evidence from animal models suggests a strong link between vascular endothelial growth factor (VGEF) and penile vasculature and erectile function because VEGF can alter the physiologic pathways involved in the regulation of penile vasomotor tone.

Aim

To investigate three VEGF polymorphisms and their link to erectile dysfunction (ED).

Methods

We enrolled 688 Taiwanese men with a mean age of 55.6 years (SD = 4.5) during a free health screening. All participants provided complete medical histories and underwent physical examinations. Fasting blood samples were obtained for biochemical analysis and hormone profiling. The allelic discrimination of three VEGF gene polymorphisms (460T/C [rs833061], 1154G/A [rs1570360], and 2578A/C [rs699947]) was performed using validated TaqMan single-nucleotide polymorphism genotyping assays.

Outcomes

Subjects underwent assessment using the simplified five-item International Index of Erectile Function to diagnose and assess ED severity.

Results

The results showed that diabetes mellitus (odds ratio [OR] = 3.27, P < .01), hypertension (OR = 3.47, P < .01), and having the VEGF 2578A allele (OR = 1.54, P = .01) were the three most independent risk factors for ED. In univariate analysis, all three VEGF polymorphisms (460C, 1154A, and 2578A) were significantly associated with a higher prevalence of coronary artery disease (P < .01) and greater frequencies of hypertension were found in carriers of the 1154A allele and the 2578A allele (P = .01). Multiple logistic regression analysis showed a significant association between VEGF 2578A allele carrier status and ED (OR = 1.54, 95% CI = 1.10∼2.15, P = .01). Furthermore, the prevalence and severity of ED were significantly increased with an increment of the 2578A allele number (P < .05).

Clinical Implications

VEGF 2578C/A gene polymorphisms could be a genetic susceptibility factor for the development of ED.

Strength and Limitation

This is the first study to investigate the genetic susceptibility of VEGF polymorphisms to ED. This study was cross-sectional with a lack of functional and molecular production investigations. Data on the association among conditions might not allow definitive conclusions about causal links.

Conclusion

This study showed that VEGF 2578A allele carriers in a Taiwanese population are at greater risk for ED.
Sexual Quality of Life and Needs for Sexology Care of Cancer Patients Admitted for Radiotherapy: A 3-Month Cross-Sectional Study in a Regional Comprehensive Reference Cancer Center
Authors: Almont Thierry , Delannes Martine , Ducassou Anne , Corman André , Bondil Pierre , Moyal Elizabeth , Schover Leslie , Huyghe Eric
Published: March 2017

Background

Providing early and better care in onco-sexuality and a better understanding of the sexual health care needs of patients before they start treatment is required.

Objective

To assess sexual quality of life and need for sexology care of patients when they are starting radiotherapy.

Design

We performed a cross-sectional study of adult patients with cancer admitted for radiotherapy treatment in a regional comprehensive cancer center.

Methods

We selected all consecutive adult patients scheduled to start radiotherapy within a 3-month period and excluded patients who could not complete the questionnaires. Patients were asked to complete the Sexual Quality of Life Questionnaire (SQoL) and a needs-assessment questionnaire.

Outcomes

Total score on the SQoL and willingness (yes or no) to get help for a sexual problem.

Results

The study sample was composed of 77 men and 123 women. The average SQoL scores were 68.4 ± 20.9 and 47.1 ± 13.0 for men and women, respectively (P < .001). Of sexually active patients, 58% had decreased frequency of intercourse or had completely stopped sexual activity after their cancer diagnosis. Half the participants wanted care for their sexual concerns. The proportion desiring specific types of care varied from 28.5% (couple counseling) to 54.5% (sexual physician) with variation by sex or type of cancer. Furthermore, 11.5% of participants declared their willingness to join support groups.

Clinical Implications

Early interventions before radiotherapy could improve sexual quality of life, particularly in women.

Strengths and Limitations

Strengths are the SQoL validated in men and women, the original window for assessment, and the study location. Limitations are the monocentric design, the potential recall bias for data before cancer diagnosis, and the fact that some patients had treatments before radiotherapy.

Conclusion

Our data suggest the need to examine the sexual health trajectory in a prospective fashion from diagnosis to survivorship.
Does the source of debt financing affect default risk?
Authors: Chiu Wan‐Chien , Wang Chih‐Wei , Peña Juan Ignacio
Published: March 2017

We examine whether the source of debt financing is important for assessments of firms’ default risk. This study reveals that during the 2007–2010 financial crisis, firms that depend mainly on financing from banks suffer higher increases in default risk than do firms with no such dependence. Conversely, firms that rely solely on financing from public debt markets do not experience significant increases in default risk. These findings suggest that the bank supply shock theory explains the transmission of financial shocks to the real economy. Finally, firms that depend on bank financing cannot offset the adverse impacts of bank lending shocks by substituting bank loans with publicly traded debt.
Civil Liberties and Human Rights in Twentieth-Century Britain
Authors: Moores Chris
Published: March 2017

The National Council for Civil Liberties (NCCL) was formed in the 1930s against a backdrop of fascism and 'popular front' movements. In this volatile political atmosphere, the aim of the NCCL was to ensure that civil liberties were a central component of political discourse. Chris Moores's new study shows how the NCCL - now Liberty - had to balance the interests of extremist allies with the desire to become a respectable force campaigning for human rights and civil liberties. From new social movements of the 1960s and 1970s to the formation of the Human Rights Act in 1998, this study traces the NCCL's development over the last eighty years. It enables us to observe shifts and continuities in forms of political mobilisation throughout the twentieth century, changes in discourse about extensions and retreats of freedoms, as well as the theoretical conceptualisation and practical protection of rights and liberties.
The size and shape of the Italian interest system between the 1980s and the present day
Authors: Lizzi Renata , Pritoni Andrea
Published: March 2017

Within interest group research, scholars following the population ecology perspective mainly look at the demographic features of populations and systems under scrutiny: density and diversity represent the main dimensions investigated. Even though, in recent years, an impressive amount of literature on this topic has been produced, there has been neither systematic analysis of, nor empirical research into, the Italian interest system so far. This article aims to address this lacuna. Following a diachronic perspective, we count how many politically active groups have populated the Italian interest system with regard to two different periods: 1984–88 and 2010–14. From 1984 to 2014 the number of interest groups almost doubled and the density of the system greatly increased; diversity, however, has remained relatively more stable.
A randomised controlled study of mindfulness meditation versus relaxation therapy in the management of tinnitus
Authors: Arif M , Sadlier M , Rajenderkumar D , James J , Tahir T
Published: March 2017

Objective:

Psychotherapeutic interventions have been adopted effectively in the management of tinnitus for a long time. This study compared mindfulness meditation and relaxation therapy for management of tinnitus.

Methods:

In this randomised controlled trial, patients were recruited for five sessions of mindfulness meditation or five sessions of relaxation therapy. Patients’ responses were evaluated using the Tinnitus Reaction Questionnaire as a primary outcome measure, and the Hospital Anxiety and Depression Scale, visual analogue scale and a health status indicator as secondary outcome measures.

Results:

A total of 86 patients were recruited. Thirty-four patients completed mindfulness meditation and 27 patients completed relaxation therapy. Statistically significant improvement was seen in all outcome measures except the health status indicator in both treatment groups. The change in treatment scores was greater in the mindfulness meditation group than in the relaxation therapy group.

Conclusion:

This study suggests that although both mindfulness meditation and relaxation therapy are effective in the management of tinnitus, mindfulness meditation is superior to relaxation therapy.
International law and its discontents: Exploring the dark sides of international law in International Relations
Authors: McKeown Ryder
Published: March 2017

International law is generally considered to be a good thing. With important exceptions, such as Critical Legal Studies, scholarship in both International Relations (IR) and International Law (IL) reinforces this ‘nice law’ assumption and therefore overlooks or underestimates the law’s negative aspects. In contrast, this article assumes the power of international law to examine how international law can have effects that are unintended, unhelpful, or even perverse. In particular, I argue that international law distorts policy- and decision-making processes in liberal democracies by eroding personal responsibility and decreasing accountability; legal expertise and legal virtues crowd out important virtues of statecraft and prudence while shrinking our capacity for sophisticated moral and political thought; and an excessive focus on law can lead to suboptimal foreign policy outcomes. Rather than law being a bad thing per se, I examine the significant strategic and moral limits of international law. This raises the need to lower our expectations of international law, carefully examine the relationship between power and international law, and political responsibility and legal ethics, and more fully embrace our own personal responsibility. The article closes by suggesting a research programme on the dark sides of international law from various theoretical perspectives.
Bat species vulnerability in Cerrado: integrating climatic suitability with sensitivity to land-use changes
Authors: MENDES POLIANA , DE MARCO PAULO
Published: March 2017

Climate variables are commonly used to predict suitability for species occurrence, but local processes, such as landscape changes, may affect habitat suitability. We identified levels of exposure to deforestation of suitable climatic areas for eight bat species in the Brazilian Cerrado and explored how sensitivity to land-use changes could reduce their persistence. We created scenarios of sensitivity to land-use changes using theoretical species persistence thresholds to natural vegetation loss in landscapes (70%, 50% and 30% of loss). We also assessed sensitivity to land-use changes using empirical data. Species are under higher exposure to land-use changes in the southern Cerrado, a region more affected by humans due to its proximity to major urban areas. Changes in land use in the Cerrado mostly affect Myotis nigricans, Artibeus cinereus and Platyrrhinus lineatus. Empirically derived scenarios encountered significant thresholds at 50% of natural vegetation loss in landscapes for Artibeus lituratus and P. lineatus. Deforestation has already affected a half of the Cerrado area, but in terms of possibly vulnerable suitable areas, a larger proportion has been lost, amounting to up to 80% of the suitable area. We propose that information on species-specific sensitivity thresholds to habitat loss and on the exposure of suitable landscapes to land-use changes can be useful to assessing species vulnerability.
Feasibility and Efficacy of Brief Computerized Training to Improve Emotion Recognition in Premanifest and Early-Symptomatic Huntington’s Disease
Authors: Kempnich Clare L. , Wong Dana , Georgiou-Karistianis Nellie , Stout Julie C.
Published: March 2017

Objectives: Deficits in the recognition of negative emotions emerge before clinical diagnosis in Huntington’s disease (HD). To address emotion recognition deficits, which have been shown in schizophrenia to be improved by computerized training, we conducted a study of the feasibility and efficacy of computerized training of emotion recognition in HD. Methods: We randomly assigned 22 individuals with premanifest or early symptomatic HD to the training or control group. The training group used a self-guided online training program, MicroExpression Training Tool (METT), twice weekly for 4 weeks. All participants completed measures of emotion recognition at baseline and post-training time-points. Participants in the training group also completed training adherence measures. Results: Participants in the training group completed seven of the eight sessions on average. Results showed a significant group by time interaction, indicating that METT training was associated with improved accuracy in emotion recognition. Conclusions: Although sample size was small, our study demonstrates that emotion recognition remediation using the METT is feasible in terms of training adherence. The evidence also suggests METT may be effective in premanifest or early-symptomatic HD, opening up a potential new avenue for intervention. Further study with a larger sample size is needed to replicate these findings, and to characterize the durability and generalizability of these improvements, and their impact on functional outcomes in HD. (JINS, 2017, 23, 314–321)
Implementing a Collaborative Working Environment Using Agile: the LexisNexis Experience
Authors: Waldron Karen
Published: March 2017

This article by Karen Waldron describes the experiences of LexisNexis in implementing Agile as a framework in product development and across the organisation. It discusses the principles of Agile, the aims of LexisNexis of greater collaboration, quicker delivery of value to customers and continuous improvement, the main activities introduced, and the benefits experienced at LexisNexis as a result. It also discusses the applicability of Agile as a framework outside of software development, as the goals are common to most organisations, and sets out the view that incorporating simple agile activities into current working practices can have incremental and short term benefit for most teams.
Palliative and end-of-life care in the masters of social work curriculum
Authors: Berkman Cathy , Stein Gary L.
Published: March 2017

Objective:

There is a shortage of social workers who have palliative care expertise. The aging U.S. population and advances in extending life for seriously ill persons require social workers in a wide range of health care and other settings with specialized palliative care expertise, as well as those with basic competence in palliative care. The objective of the present study was to document course content on palliative care in MSW programs in the United States and Canada.

Method:

A cross-sectional design with an online questionnaire was used. All 248 accredited MSW programs in the United States and 32 programs in Canada were invited to participate. The measures included the characteristics of the courses on palliative care.

Results:

Of the 105 participating programs, only 10 had courses dedicated to palliative care, 9 of which were part of a specialization/certificate program. Few programs had plans to develop a dedicated course. There were 106 courses in 63 MSW programs with some content on palliative care. The majority of these had <25%, and few had at least 50%, of palliative care content.

Significance of Results:

Curricula are needed for preparing MSW graduates for specialty hospice and palliative care practice and non-specialty practice. While there are practice competencies for specialty practitioners, consensus on a core curriculum for all MSW students would be beneficial. Consensus on basic palliative care knowledge and skills for non-specialty social workers in health care and other settings and subsequent curriculum development are also needed. Innovative ways in which to introduce basic and more specialized content on palliative care into the already-crowded MSW curricula will be needed.
Situational and Dispositional Factors that Predict Motivation: a Multilevel Study
Authors: Pineda-Espejel Heriberto Antonio , López-Walle Jeanette , Tomás Inés
Published: March 2017

This study aimed to test a multilevel mediation model which examined the relationship between the perceived motivational climate created by coaches at team level and motivational regulations towards sport at individual level, as mediated by individual goal orientations. 211 university athletes from 20 teams training in different types of sport completed a battery of instruments that measured the variables included in the model. The statistics significance level was .05. Results of the multilevel mediation model revealed that the task-involving climate at team level positively predicted individual task orientation (γ01 = .77, p < .001) and autonomous motivation for sport practice (γ01 = .68, p = .03). Task orientation positively predicts the autonomous motivation (γ10 =.51, p < .01), and inversely the non motivation (γ10 = –.76, p < .001). Also task orientation partially mediated the relationship between task-involving climate and autonomous motivation (b1b2 = .39; 95% CI = [.11, .68]; τ = .68, p < .05), and fully mediated the relationship between task-involving climate and amotivation (b1b2 = –.58; 95% CI = [–.92, –.25]; τ = –.62, p >.05). The results are in line with previous research that have focused in the study of motivational climate at individual level, but the present study make a novel contribution by providing the perspective of a multilevel mediation model and thereby clarifying the phenomenon at team level.
miR-491-5p, mediated by Foxi1, functions as a tumor suppressor by targeting Wnt3a/β-catenin signaling in the development of gastric cancer
Authors: Sun Ruifang , Liu Zhigang , Tong Dongdong , Yang Yang , Guo Bo , Wang Xiaofei , Zhao Lingyu , Huang Chen
Published: March 2017

Accumulated evidence has suggested that microRNAs (miRNAs) have an important role in tumor development and progression by regulating diverse signaling pathways. However, the precise role of miRNAs in gastric cancer (GC) has not been elucidated. In this study, we describe the function and regulation network of miR-491-5p in GC. miR-491-5p is frequently downregulated in GC tissues compared with adjacent non-cancerous tissues. Forced expression of miR-491-5p significantly inhibits proliferation and colony formation, and promotes apoptosis in GC cells. Through bioinformatic analysis and luciferase assays, we confirm that miR-491-5p targets Wnt3a. Silencing Wnt3a inhibits cell proliferation and induces apoptosis. Similarly, restoration of Wnt3a counteracts the effects of miR-491-5p expression. Moreover, bioinformatic and luciferase assays indicate that the expression of miR-491-5p is regulated by Foxi1, which binds to its promoter and activates miR-491-5p expression. In conclusion, to the best of our knowledge, our findings are the first to demonstrate that Foxi1 is a key player in the transcriptional control of miR-491-5p and that miR-491-5p acts as an anti-oncogene by targeting Wnt3a/β-catenin signaling in GC. Our study reveals that Foxi1/miR-491-5p/Wnt3a/β-catenin signaling is critical in the progression of GC. Targeting the pathway described in this study may open up new prospects to restrict the progression of GC.
Overexpression of EphB2 in hippocampus rescues impaired NMDA receptors trafficking and cognitive dysfunction in Alzheimer model
Authors: Hu Rui , Wei Pan , Jin Lu , Zheng Teng , Chen Wen-Yu , Liu Xiao-Ya , Shi Xiao-Dong , Hao Jing-Ru , Sun Nan , Gao Can
Published: March 2017

Alzheimer’s disease (AD) is a progressive neurodegenerative disease, which affects more and more people. But there is still no effective treatment for preventing or reversing the progression of the disease. Soluble amyloid-beta (Aβ) oligomers, also known as Aβ-derived diffusible ligands (ADDLs) play an important role in AD. Synaptic activity and cognition critically depend on the function of glutamate receptors. Targeting N-methyl-D-aspartic acid (NMDA) receptors trafficking and its regulation is a new strategy for AD early treatment. EphB2 is a key regulator of synaptic localization of NMDA receptors. Aβ oligomers could bind to the fibronectin repeats domain of EphB2 and trigger EphB2 degradation in the proteasome. Here we identified that overexpression of EphB2 with lentiviral vectors in dorsal hippocampus improved impaired memory deficits and anxiety or depression-like behaviors in APPswe/PS1-dE9 (APP/PS1) transgenic mice. Phosphorylation and surface expression of GluN2B-containing NMDA receptors were also improved. Overexpression of EphB2 also rescued the ADDLs-induced depletion of the expression of EphB2 and GluN2B-containing NMDA receptors trafficking in cultured hippocampal neurons. These results suggest that improving the decreased expression of EphB2 and subsequent GluN2B-containing NMDA receptors trafficking in hippocampus may be a promising strategy for AD treatment.
Novel prosurvival function of Yip1A in human cervical cancer cells: constitutive activation of the IRE1 and PERK pathways of the unfolded protein response
Authors: Taguchi Yuki , Horiuchi Yuta , Kano Fumi , Murata Masayuki
Published: March 2017

Cancer cells are under chronic endoplasmic reticulum (ER) stress due to hypoxia, low levels of nutrients, and a high metabolic demand for proliferation. To survive, they constitutively activate the unfolded protein response (UPR). The inositol-requiring protein 1 (IRE1) and protein kinase RNA-like ER kinase (PERK) signaling branches of the UPR have been shown to have cytoprotective roles in cancer cells. UPR-induced autophagy is another prosurvival strategy of cancer cells, possibly to remove misfolded proteins and supply nutrients. However, the mechanisms by which cancer cells exploit the UPR and autophagy machinery to promote survival and the molecules that are essential for these processes remain to be elucidated. Recently, a multipass membrane protein, Yip1A, was shown to function in the activation of IRE1 and in UPR-induced autophagy. In the present study, we explored the possible role of Yip1A in activation of the UPR by cancer cells for their survival, and found that depletion of Yip1A by RNA interference (RNAi) induced apoptotic cell death in HeLa and CaSki cervical cancer cells. Intriguingly, Yip1A was found to activate the IRE1 and PERK pathways of the UPR constitutively in HeLa and CaSki cells. Yip1A mediated the phosphorylation of IRE1 and also engaged in the transcription of PERK. The activation of these signaling pathways upregulated the expression of anti-apoptotic proteins and autophagy-related proteins. These events might enhance resistance to apoptosis and promote cytoprotective autophagy in HeLa and CaSki cells. The present study is the first to uncover a key prosurvival modulator, Yip1A, which coordinates IRE1 signaling with PERK signaling to support the survival of HeLa and CaSki cervical cancer cells.
Madecassic acid, the contributor to the anti-colitis effect of madecassoside, enhances the shift of Th17 toward Treg cells via the PPARγ/AMPK/ACC1 pathway
Authors: Xu Xiaotian , Wang Yuhui , Wei Zhifeng , Wei Wenhui , Zhao Peng , Tong Bei , Xia Yufeng , Dai Yue
Published: March 2017

The imbalance between Th17 and Treg cells substantially contributes to the intestinal immune disturbance and subsequent tissue injury in ulcerative colitis. The triterpenoid-rich fraction of Centella asiatica was able to ameliorate dextran sulfate sodium-induced colitis in mice. Here we explored its active ingredient and underlying mechanism with a focus on restoring the Th17/Treg balance. The four main triterpenoids occurring in C. asiatica were shown to attenuate colitis in mice by oral administration. The most effective ingredient madecassoside lost anti-colitis effect when applied topically in the colon, and madecassic acid was recognized to be the active form of madecassoside. Oral administration of madecassic acid decreased the percentage of Th17 cells and downregulated the expression of RORγt, IL-17A, IL-17F, IL-21 and IL-22 and increased the percentage of Treg cells and the expression of Foxp3 and IL-10 in the colons of mice with colitis, but it did not affect Th1 and Th2 cells. Under Th17-polarizing conditions, madecassic acid downregulated ACC1 expression and enhanced the shift of Th17 cells toward Treg cells, but it did not affect the differentiation of Treg cells under Treg-polarizing conditions. Both compound C and AMPK siRNA inhibited the madecassic acid-mediated downregulation of ACC1 expression and shift of Th17 cells to Treg cells under Th17-polarizing conditions. GW9662, T0070907 and PPARγ siRNA blocked the effect of madecassic acid on AMPK activation, ACC1 expression and shift of Th17 cells to Treg cells. Furthermore, madecassic acid was identified as a PPARγ agonist, as it promoted PPARγ transactivation. The correlation between activation of PPARγ and AMPK, downregulation of ACC1 expression, restoration of Th17/Treg balance and attenuation of colitis by madecassic acid was validated in mice with DSS-induced colitis. In conclusion, madecassic acid was the active form of madecassoside in ameliorating colitis by restoring the Th17/Treg balance via regulating the PPARγ/AMPK/ACC1 pathway.
Negative regulators and their mechanisms in NLRP3 inflammasome activation and signaling
Authors: Kim Jin Kyung , Jin Hyo Sun , Suh Hyun‐Woo , Jo Eun‐Kyeong
Published: March 2017

Inflammasomes are cytosolic multiprotein complexes that cause the release of biologically active interleukin‐1β. The best‐characterized inflammasome is the NLRP3 (nucleotide‐binding domain, leucine‐rich‐containing family, pyrin domain‐containing‐3 or Nod‐like receptor protein 3) inflammasome. The NLRP3 inflammasome forms an assembly consisting of the ASC (apoptosis‐associated speck‐like protein containing a C‐terminal caspase recruitment domain) adaptor protein and the effector, caspase‐1 (cysteine‐dependent aspartate‐directed protease‐1). Numerous agents and ligands derived from pathogens, modified self‐cells and the environment induce NLRP3 inflammasome complex formation. NLRP3 inflammasome activation is tightly controlled at the transcriptional and post‐translational levels to prevent unwanted excessive inflammation. Recent studies have highlighted the roles and mechanisms of several negative regulators that inhibit the assembly of NLRP3 inflammasome complexes and suppress inflammatory responses. The identification and characterization of new players in the regulation of NLRP3 inflammasome may lead to the development of inflammasome‐targeting therapeutics against various inflammatory diseases related to NLRP3 inflammasome‐associated pathogenesis.
Sequence-selective encapsulation and protection of long peptides by a self-assembled FeII8L6 cubic cage
Authors: Mosquera Jesús , Szyszko Bartosz , Ho Sarah K. Y. , Nitschke Jonathan R.
Published: March 2017

Self-assembly offers a general strategy for the preparation of large, hollow high-symmetry structures. Although biological capsules, such as virus capsids, are capable of selectively recognizing complex cargoes, synthetic encapsulants have lacked the capability to specifically bind large and complex biomolecules. Here we describe a cubic host obtained from the self-assembly of FeII and a zinc-porphyrin-containing ligand. This cubic cage is flexible and compatible with aqueous media. Its selectivity of encapsulation is driven by the coordination of guest functional groups to the zinc porphyrins. This new host thus specifically encapsulates guests incorporating imidazole and thiazole moieties, including drugs and peptides. Once encapsulated, the reactivity of a peptide is dramatically altered: encapsulated peptides are protected from trypsin hydrolysis, whereas physicochemically similar peptides that do not bind are cleaved.
Detection of dietetically absorbed maize-derived microRNAs in pigs
Authors: Luo Yi , Wang Pengjun , Wang Xun , Wang Yuhao , Mu Zhiping , Li Qingzhi , Fu Yuhua , Xiao Juan , Li Guojun , Ma Yao , Gu Yiren , Jin Long , Ma Jideng , Tang Qianzi , Jiang Anan , Li Xuewei , Li Mingzhou
Published: March 2017

MicroRNAs are a class of small RNAs that are important in post-transcriptional gene regulation in animals and plants. These single-stranded molecules are widely distributed in organisms and influence fundamental biological processes. Interestingly, recent studies have reported that diet-derived plant miRNAs could regulate mammalian gene expression, and these studies have broadened our view of cross-kingdom communication. In the present study, we evaluated miRNA levels in cooked maize-containing chow diets, and found that plant miRNAs were resistant to the harsh cooking conditions to a certain extent. After feeding fresh maize to pigs (7 days), maize-derived miRNAs could be detected in porcine tissues and serum, and the authenticity of these plant miRNAs was confirmed by using oxidization reactions. Furthermore, in vivo and in vitro experiments demonstrated that dietary maize miRNAs could cross the gastrointestinal tract and enter the porcine bloodstream. In the porcine cells, we found that plant miRNAs are very likely to specifically target their endogenous porcine mRNAs and influence gene expression in a fashion similar to that of mammalian miRNAs. Our results indicate that maize-derived miRNAs can cross the gastrointestinal tract and present in pigs, and these exogenous miRNAs have the potential to regulate mammalian gene expression.
Metabolomics reveals biotic and abiotic elicitor effects on the soft coral Sarcophyton ehrenbergi terpenoid content
Authors: Farag Mohamed A. , Al-Mahdy Dalia A. , Meyer Achim , Westphal Hildegard , Wessjohann Ludger A.
Published: March 2017

The effects of six biotic and abiotic elicitors, i.e. MeJA (methyl jasmonate), SA (salicylic acid), ZnCl2, glutathione andβ-glucan BG (fungal elicitor), and wounding, on the secondary metabolite accumulation in the soft coralSarcophyton ehrenbergiwere assessed. Upon elicitation, metabolites were extracted and analysed by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Except for MeJA, no differences in photosynthetic efficiency were observed after treatments, suggesting the absence of a remarkable stress on primary production. Chemometric analyses of UPLC-MS data showed clear segregation of SA and ZnCl2elicited samples at 24 and 48 h post elicitation. Levels of acetylated diterpene and sterolviz., sarcophytonolide I and cholesteryl acetate, was increased in ZnCl2and SA groups, respectively, suggesting an activation of specific acetyl transferases. Post elicitation, sarcophytonolide I level increased 132 and 17-folds at 48 h in 0.1 mM SA and 1 mM ZnCl2groups, respectively. Interestingly, decrease in sarcophine, a major diterpene was observed only in response to ZnCl2, whereas no change was observed in sesquiterpene content following treatments. To the best of our knowledge, this study provides the first documentation for elicitation effects on a soft corals secondary metabolome and suggests that SA could be applied to increase diterpenoid levels in corals.
Suppression of FOXM1 Transcriptional Activities via a Single-Stranded DNA Aptamer Generated by SELEX
Authors: Xiang Qin , Tan Guixiang , Jiang Xia , Wu Kuangpei , Tan Weihong , Tan Yongjun
Published: March 2017

The transcription factor FOXM1 binds to its consensus sequence at promoters through its DNA binding domain (DBD) and activates proliferation-associated genes. The aberrant overexpression of FOXM1 correlates with tumorigenesis and progression of many cancers. Inhibiting FOXM1 transcriptional activities is proposed as a potential therapeutic strategy for cancer treatment. In this study, we obtained a FOXM1-specific single stranded DNA aptamer (FOXM1 Apt) by SELEX with a recombinant FOXM1 DBD protein as the target of selection. The binding of FOXM1 Apt to FOXM1 proteins were confirmed with electrophoretic mobility shift assays (EMSAs) and fluorescence polarization (FP) assays. Phosphorthioate-modified FOXM1 Apt (M-FOXM1 Apt) bound to FOXM1 as wild type FOXM1 Apt, and co-localized with FOXM1 in nucleus. M-FOXM1-Apt abolished the binding of FOXM1 on its consensus binding sites and suppressed FOXM1 transcriptional activities. Compared with the RNA interference of FOXM1 in cancer cells, M-FOXM1 Apt repressed cell proliferation and the expression of FOXM1 target genes without changing FOXM1 levels. Our results suggest that the obtained FOXM1 Apt could be used as a probe for FOXM1 detection and an inhibitor of FOXM1 transcriptional functions in cancer cells at the same time, providing a potential reagent for cancer diagnosis and treatment in the future.
Electron tomographic analysis reveals ultrastructural features of mitochondrial cristae architecture which reflect energetic state and aging
Authors: Jiang Yi-fan , Lin Shao-syuan , Chen Jing-min , Tsai Han-zen , Hsieh Tao-shih , Fu Chi-yu
Published: March 2017

Within mitochondria, the ability to produce energy relies upon the architectural hallmarks of double membranes and cristae invaginations. Herein, we describe novel features of mitochondrial cristae structure, which correspond to the energetic state of the organelle. In concordance with high-energy demand, mitochondria of Drosophila indirect flight muscle exhibited extensive intra-mitochondrial membrane switches between densely packed lamellar cristae that resulted in a spiral-like cristae network and allowed for bidirectional matrix confluency. This highly interconnected architecture is expected to allow rapid equilibration of membrane potential and biomolecules across integrated regions. In addition, mutant flies with mtDNA replication defect and an accelerated aging phenotype accumulated mitochondria that contained subsections of swirling membrane alongside normal cristae. The swirling membrane had impaired energy production capacity as measured by protein composition and function. Furthermore, mitochondrial fusion and fission dynamics were affected in the prematurely aged flies. Interestingly, the normal cristae that remained in the mitochondria with swirling membranes maintained acceptable function that camouflaged them from quality control elimination. Overall, structural features of mitochondrial cristae were described in three-dimension from serial section electron tomographic analysis which reflect energetic state and mtDNA-mediated aging.
Domain-specific interactions between MLN8237 and human serum albumin estimated by STD and WaterLOGSY NMR, ITC, spectroscopic, and docking techniques
Authors: Yang Hongqin , Liu Jiuyang , Huang Yanmei , Gao Rui , Tang Bin , Li Shanshan , He Jiawei , Li Hui
Published: March 2017

Alisertib (MLN8237) is an orally administered inhibitor of Aurora A kinase. This small-molecule inhibitor is under clinical or pre-clinical phase for the treatment of advanced malignancies. The present study provides a detailed characterization of the interaction of MLN8237 with a drug transport protein called human serum albumin (HSA). STD and WaterLOGSY nuclear magnetic resonance (NMR)-binding studies were conducted first to confirm the binding of MLN8237 to HSA. In the ligand orientation assay, the binding sites of MLN8237 were validated through two site-specific spy molecules (warfarin sodium and ibuprofen, which are two known site-selective probes) by using STD and WaterLOGSY NMR competition techniques. These competition experiments demonstrate that both spy molecules do not compete with MLN8237 for the specific binding site. The AutoDock-based blind docking study recognizes the hydrophobic subdomain IB of the protein as the probable binding site for MLN8237. Thermodynamic investigations by isothermal titration calorimetry (ITC) reveal that the non-covalent interaction between MLN8237 and HSA (binding constant was approximately 105 M−1) is driven mainly by favorable entropy and unfavorable enthalpy. In addition, synchronous fluorescence, circular dichroism (CD), and 3D fluorescence spectroscopy suggest that MLN8237 may induce conformational changes in HSA.
NMDA receptor antagonism with novel indolyl, 2-(1,1-Dimethyl-1,3-dihydro-benzo[e]indol-2-ylidene)-malonaldehyde, reduces seizures duration in a rat model of epilepsy
Authors: Rothan Hussin A. , Amini Elham , Faraj Fadihl L. , Golpich Mojtaba , Teoh Teow Chong , Gholami Khadijeh , Yusof Rohana
Published: March 2017

N-methyl-D-aspartate receptors (NMDAR) play a central role in epileptogensis and NMDAR antagonists have been shown to have antiepileptic effects in animals and humans. Despite significant progress in the development of antiepileptic therapies over the previous 3 decades, a need still exists for novel therapies. We screened an in-house library of small molecules targeting the NMDA receptor. A novel indolyl compound, 2-(1,1-Dimethyl-1,3-dihydro-benzo[e]indol-2-ylidene)-malonaldehyde, (DDBM) showed the best binding with the NMDA receptor and computational docking data showed that DDBM antagonised the binding sites of the NMDA receptor at lower docking energies compared to other molecules. Using a rat electroconvulsive shock (ECS) model of epilepsy we showed that DDBM decreased seizure duration and improved the histological outcomes. Our data show for the first time that indolyls like DDBM have robust anticonvulsive activity and have the potential to be developed as novel anticonvulsants.
Hot-Volumes as Uniform and Reproducible SERS-Detection Enhancers in Weakly-Coupled Metallic Nanohelices
Authors: Caridad José M. , Winters Sinéad , McCloskey David , Duesberg Georg S. , Donegan John F. , Krstić Vojislav
Published: March 2017

Reproducible and enhanced optical detection of molecules in low concentrations demands simultaneously intense and homogeneous electric fields acting as robust signal amplifiers. To generate such sophisticated optical near-fields, different plasmonic nanostructures were investigated in recent years. These, however, exhibit either high enhancement factor (EF) or spatial homogeneity but not both. Small interparticle gaps or sharp nanostructures show enormous EFs but no near-field homogeneity. Meanwhile, approaches using rounded and separated monomers create uniform near-fields with moderate EFs. Here, guided by numerical simulations, we show how arrays of weakly-coupled Ag nanohelices achieve both homogeneous and strong near-field enhancements, reaching even the limit forreproducible detection of individual molecules. The unique near-field distribution of a single nanohelix consists of broad hot-spots, merging with those from neighbouring nanohelices in specific array configurations and generating a wide and uniform detection zone (“hot-volume”). We experimentally assessed these nanostructures via surface-enhanced Raman spectroscopy, obtaining a corresponding EF of ~107 and a relative standard deviation <10%. These values demonstrate arrays of nanohelices as state-of-the-art substrates for reproducible optical detection as well as compelling nanostructures for related fields such as near-field imaging.
Disparities in correlating microstructural to nanostructural preservation of dinosaur femoral bones
Authors: Kim Jung-Kyun , Kwon Yong-Eun , Lee Sang-Gil , Lee Ji-Hyun , Kim Jin-Gyu , Huh Min , Lee Eunji , Kim Youn-Joong
Published: March 2017

Osteohistological researches on dinosaurs are well documented, but descriptions of direct correlations between the bone microstructure and corresponding nanostructure are currently lacking. By applying correlative microscopy, we aimed to verify that well-preserved osteohistological features correlate with pristine fossil bone nanostructures from the femoral bones ofKoreanosaurus boseongensis. The quality of nanostructural preservation was evaluated based on the preferred orientation level of apatite crystals obtained from selected area electron diffraction (SAED) patterns and by measuring the “arcs” from the {100} and {002} diffraction rings. Unlike our expectations, our results revealed that well-preserved microstructures do not guarantee pristine nanostructures and vice versa. Structural preservation of bone from macro- to nanoscale primarily depends on original bioapatite density, and subsequent taphonomical factors such as effects from burial, pressure, influx of external elements and the rate of diagenetic alteration of apatite crystals. Our findings suggest that the efficient application of SAED analysis opens the opportunity for comprehensive nanostructural investigations of bone.