bluuebunny/crossref_metadata_2025 huggingface dataset:
Long distance behavior of O(N)-model correlators in de Sitter space and the resummation of secular terms
Authors: Nacir Diana López , Mazzitelli Francisco D. , Trombetta Leonardo G.
Published: October 2018

Abstract

We analyze the long distance behavior of the two-point functions for an interacting scalarO(N) model in de Sitter spacetime. Following our previous work, this behavior is analyzed by analytic continuation of the Euclidean correlators, which are computed by treating the homogeneous zero mode exactly and using a partial resummation of the interactions between the zero and the non-zero modes. We focus on massless fields and present an alternative derivation of our method, which involves a double expansion in 1/Nand the coupling constant of the theory. This derivation is simpler than the previous one and can be directly extended for fields with negative squared-mass. We extend our previous results by computing the long wavelength limit of the two-point functions at next-to-leading order in 1/Nand at leading order in the coupling constant, which involves a further resummation of Feynman diagrams (needed when the two-point functions are analitically continued). We prove that, after this extra resummation, the two-point functions vanish in the long distance limit.
Matter effect of light sterile neutrino: an exact analytical approach
Authors: Li Wei , Ling Jiajie , Xu Fanrong , Yue Baobiao
Published: October 2018

Abstract

The light sterile neutrino, if it exists, will give additional contribution to matter effect when active neutrinos propagate through terrestrial matter. In the simplest 3+1 scheme, three more rotation angles and two more CP-violating phases in lepton mixing matrix make the interaction complicated formally. In this work, the exact analytical expressions for active neutrino oscillation probabilities in terrestrial matter, including sterile neutrino contribution, are derived. It is pointed out that this set of formulas contain information both in matter and in vacuum, and can be easily tuned by choosing related parameters. Based on the generic exact formulas, we present oscillation probabilities of typic medium and long baseline experiments. Taking NOνA experiment as an example, we show that in particular parameter space sterile neutrino gives important contribution to terrestrial matter effect, and Dirac phases play a vital role.
Undocumented, Unafraid, and Precarious: Thinking through Conceptions of Civics by Undocumented Activists
Authors: Tirado Jesús A.
Published: October 2018

With concerns about political apathy, it might be worth turning to a group that is challenging the political discourse and confronting institutions and policies head on. This article explores the ideas of two undocumented activists who are working to change the laws and politics that affect them. Using their work and dedication, this article discusses their dedication and their ideas for creating a new basis for a civics curriculum that goes beyond information and instead places other values at the center of education.
Oncolytic virus immunotherapies in ovarian cancer: moving beyond adenoviruses
Authors: Hoare Joseph , Campbell Nicola , Carapuça Elisabete
Published: October 2018

Ovarian cancer is the 5th most common cancer in UK women with a high relapse rate. The overall survival for ovarian cancer has remained low for decades prompting a real need for new therapies. Recurrent ovarian cancer remains confined in the peritoneal cavity in >80% of the patients, providing an opportunity for locoregional administration of novel therapeutics, including gene and viral therapy approaches. Immunotherapy is an expanding field, and includes oncolytic viruses as well as monoclonal antibodies, immune checkpoint inhibitors, and therapeutic vaccines.

Oncolytic viruses cause direct cancer cell cytolysis and immunogenic cell death and subsequent release of tumor antigens that will prime for a potent tumor-specific immunity. This effect may be further enhanced when the viruses are engineered to express, or coadministered with, immunostimulatory molecules. Currently, the most commonly used and well-characterized vectors utilized for virotherapy purposes are adenoviruses. They have been shown to work synergistically with traditional chemotherapy and radiotherapy and have met with success in clinical trials. However, pre-existing immunity and poor in vivo models limit our ability to fully investigate the potential of oncolytic adenovirus as effective immunotherapies which in turn fosters the need to develop alternative viral vectors. In this review we cover recent advances in adenovirus-based oncolytic therapies targeting ovarian cancer and recent advances in mapping immune responses to oncolytic virus therapies in ovarian cancer.
Evaluation of the pelvic floor muscles training in older women with urinary incontinence: a systematic review
Authors: Rocha Flávia , Carvalho Joana , Jorge Natal Renato , Viana Rui
Published: October 2018

Background:

Urinary incontinence (UI) is defined as any involuntary urine loss that predominantly affects older women. There is evidence that pelvic floor muscles training (PFMT) program is effective on the treatment of pelvic floor (PF) dysfunctions and is considered to be first-line treatment. The evaluation of pelvic floor muscles (PFM) function and strength is central to validate the effectiveness of the training protocol in UI decrease. The Oxford Grading Scale and manometry are fundamental to evaluate the PFM function and strength.

Objective:

The aim of the study was to systematize the scientific evidence about the effects of PFMT in older women, assessing the PF function and strength through Oxford Grading Scale and manometry.

Methods:

The research of randomized controlled clinical trials was performed through B-on, EBSCO, PEDro, Pubmed, and SciELO data carried out from 2003 to 2016.

Results:

A total of 35 studies were identified, 26 of these were selected and fully analyzed. From the analyzed studies (n = 26), 20 were excluded for not meeting the criteria for inclusion, and only 6 studies were classified as high methodological quality, scoring an overall 4 points according the PEDro scale.

Conclusion:

The PFMT seems to be effective in treating UI in older women; the Oxford Grading Scale and manometry are considered the most reliable in the random and controlled clinical trials results. However, future investigations with high methodological quality with older women are necessary to support these results.
FARMER PERCEPTIONS OF PRECISION AGRICULTURE TECHNOLOGY BENEFITS
Authors: THOMPSON NATHANAEL M. , BIR COURTNEY , WIDMAR DAVID A. , MINTERT JAMES R.
Published: October 2018

The objective of this research was to evaluate producers’ perspectives of four key precision agriculture technologies (variable rate fertilizer application, precision soil sampling, guidance and autosteer, and yield monitoring) in terms of the benefits they provide to their farms (increased yield, reduced production costs, and increased convenience) using a best-worst scaling choice experiment. Results indicate that farmers’ perceptions of the benefits derived from various precision agriculture technologies are heterogeneous. To better understand farmers’ adoption decisions, or lack thereof, it is important to first understand their perceptions of the benefits precision agriculture technologies provide.
Mental illness in primary care: a narrative review of patient, GP and population factors that affect prescribing rates
Authors: Tobin H. , Bury G. , Cullen W.
Published: October 2018

Background

Mental illness poses a large and growing disease burden worldwide. Its management is increasingly provided by primary care. The prescribing of psychotropic drugs in general practice has risen in recent decades, and variation in prescribing rates has been identified by a number of studies. It is unclear which factors lead to this variation.

Aim

To describe the variables that cause variation in prescribing rates for psychotropic drugs between general practices.

Methods

A narrative review was conducted in January 2018 by searching electronic databases using the PRISMA statement. Studies investigating causal factors for variation in psychotropic prescribing between at least two general practice sites were eligible for inclusion.

Results

Ten studies met the inclusion criteria. Prescribing rates varied considerably between practices. Positive associations were found for many variables, including social deprivation, ethnicity, patient age and gender, urban location, co-morbidities, chronic diseases and GP demographics. However studies show conflicting findings, and no single regression model explained more than 57% of the variation in prescribing rates.

Discussion

There is no consensus on the factors that most predict prescribing rates. Most research was conducted in countries with central electronic databases, such as the United Kingdom; it is unclear whether these findings apply in other healthcare systems. More research is needed to determine the variables that explain prescribing rates for psychotropic medications.
Hyperkinetic disorder in a community service for people with intellectual disability
Authors: Patel Sonn , Yacoub Evan
Published: October 2018

Background

There appears to be a higher rate of prevalence of hyperkinetic disorder in the intellectual disability (ID) population, although there is a large variability in rates in previous studies. Hyperkinetic disorder can be a challenge to diagnose in a population with ID and can present a barrier to the development of the activities of daily living in an already vulnerable population.

Objectives

Our objective was to examine the point prevalence of hyperkinetic disorder in the ID population in a community ID service and also to determine the prevalence of hyperkinetic disorder based on the level of ID.

Methods

A cross-sectional review of the Online Information Service ‘OLIS’ database was undertaken to establish the total number of patients with ID and those with comorbid hyperkinetic disorder. The overall point prevalence and prevalence based on the level of ID was calculated from the collected data.

Results

The point prevalence of hyperkinetic disorder in the population with ID was similar to that found in studies in the general population at 3.1% in adults and 32.6% in children. When divided by the level of disability, the calculated point prevalence in both adults and children was highest in the population with mild ID and decreased as the level of disability increased.

Conclusion

This report contributes to previous research establishing the rates of hyperkinetic disorder in an ID population and establishes the point prevalence of hyperkinetic disorder in individuals diagnosed with ID in a clinical sample.
Pollution, Infectious Disease, and Mortality: Evidence from the 1918 Spanish Influenza Pandemic
Authors: Clay Karen , Lewis Joshua , Severnini Edson
Published: October 2018

The 1918 Influenza Pandemic killed millions worldwide and hundreds of thousands in the United States. This article studies the impact of air pollution on pandemic mortality. The analysis combines a panel dataset on infant and all-age mortality with a novel measure of air pollution based on the burning of coal in a large sample of U.S. cities. We estimate that air pollution contributed significantly to pandemic mortality. Cities that used more coal experienced tens of thousands of excess deaths in 1918 relative to cities that used less coal with similar pre-pandemic socioeconomic conditions and baseline health. Factors related to poverty, public health, and the timing of onset also affected pandemic mortality. The findings support recent medical evidence on the link between air pollution and influenza infection, and suggest that poor air quality was an important cause of mortality during the pandemic.
Opportunities for Corrective Feedback During Study Abroad: A Mixed Methods Approach
Authors: Bryfonski Lara , Sanz Cristina
Published: October 2018

The provision of corrective feedback during oral interaction has been deemed an essential element for successful second language acquisition (Gass & Mackey, 2015a). However, corrective feedback—especially corrective feedback provided by peer interlocutors—remains understudied in naturalistic settings. The present mixed methods study aimed to identify the target and type of corrective feedback provided by both native-speaker and peer interlocutors during conversation groups while abroad. U.S. study abroad students (N= 19) recorded group conversations with native speakers (N= 10) at the beginning, middle, and end of a 6-week stay in Barcelona, Spain. Results indicate a significant decrease in the provision of corrective feedback by both native speakers and peer learners over the course of the program. Qualitative analyses revealed that both learners and natives alike engage in negotiations for meaning throughout the program, which for learners resulted in successful recall on tailor-made quizzes. The use of the first language by both the study abroad students and the native speakers promoted these opportunities in some instances. Results are discussed in terms of their contribution to the study abroad literature as well as to research into the effects of feedback on second language development.
Task-Based Learning in Task-Based Teaching: Training Teachers of Chinese as a Foreign Language
Authors: Han ZhaoHong
Published: October 2018

Task-based language teaching (TBLT) is increasingly becoming known for its distinct edge in developing learners’ functional competence. Although its potential in promoting content learning has yet to be realized and explored, it should be high, given TBLT's primary attention to meaning. To what extent does the potential play out in foreign language teacher education, a domain involving much content learning, is both an intellectually stimulating and practically meaningful question. This article reports on a semester-long study investigating task-based learning in a Chinese language teacher-training program that promotes TBLT. The participants were three Chinese-speaking trainees, who, while being exposed to TBLT, performed ongoing tasks. Data from one task—writing weekly reading journals—were analyzed for both content and language, quantitatively (using robust automated tools) and qualitatively. The results show tangible gains on both counts—understanding TBLT (content) and the ability to articulate it (language). The conceptual and methodological implications of the findings are discussed for future research.
Learning Chinese through Contextualized Language Practices in Study Abroad Residence Halls: Two Case Studies
Authors: Kinginger Celeste , Wu Qian
Published: October 2018

A key question about study abroad concerns the relative benefits and qualities of various living arrangements as sites for learning language and culture. A widely shared assumption seems to be that students choosing homestays enjoy more opportunities for engagement in high-quality interactive settings than do those who opt for residence halls. However, research on outcomes has to date produced only weak evidence for a homestay advantage, suggesting a need to understand the nature of language socialization practices in various living situations. While a number of studies have examined the nature of homestay interaction, only a few have focused on language use in residence halls or other settings where students may interact with peers who are expert second language users. Informed by a Vygotskian approach to the study of development, this article examines the specific qualities of contextualized language practices through two case studies of U.S.-based learners of Mandarin in Shanghai and their Chinese roommates. In the first case, a friendly relationship emerged from routine participation in emotionally charged conversational narrative. In the second, both participants’ interest in verbal play and humor led to enjoyment as well as profoundly intercultural dialogue. In each case, there is evidence to show that all parties enjoyed opportunities to learn. These findings suggest that residence halls can be very significant contexts for learning in study abroad settings.
Language Use Across International Contexts: Shaping the Minds of L2 Speakers
Authors: Kroll Judith F. , Dussias Paola E. , Bajo María Teresa
Published: October 2018

Bilingualism is a complex life experience. Second language (L2) learning and bilingualism take place in many different contexts. To develop a comprehensive account of dual-language experience requires research that examines individuals who are learning and using two languages in both the first language (L1) and second language (L2) environments. In this article, we review studies that exploit the presence of an international research network on bilingualism to investigate the role of the environment and some the unique characteristics of L2 learning and bilingual language usage in different locations. We ask how the context of learning affects the acquisition of the L2 and the ability to control the use of each language, how language processing is changed by the patterns of language usage in different places (e.g., whether bilinguals have been immersed in the L2 environment for an extended period of time or whether they code-switch), and how the bilingualism of the community itself influences learning and language use.
Experiences of International Language Teachers at a Turkish University
Authors: Kahraman Hasibe , Pipes Ashleigh
Published: October 2018

Using a multiple case study approach, this short research article describes the experiences of three teachers (of German, French, and Korean) in a Turkish university where English is also mandatorily taught. Three themes common to the participants’ experiences emerged: use of the Turkish language, integrative adaptability, and international self-awareness. We suggest that understanding these themes may help teachers, students, and administrators better understand the rich and potentially unique fonts of knowledge that international teachers could bring into Turkish language classrooms in a university context.
Longitudinal effects of acculturation and enculturation on mental health: Does the measure matter?
Authors: Meca Alan , Schwartz Seth J. , Martinez Charles R. , McClure Heather H.
Published: October 2018

A great deal of research has focused on acculturation and enculturation, which represent the processes of adapting to a new culture. Despite this growing literature, results have produced inconsistent findings that may be attributable to differences in terms of the instruments used to assess acculturation and enculturation. Utilizing a 3-year longitudinal data set (with 1-year lags between assessments), the present study explored the psychometric properties of the Bicultural Involvement Questionnaire—Short Version (BIQ-S) and the Acculturation Rating Scale for Mexican Americans II (ARSMA-II) and examined the overlap between changes in these measures as they relate to internalizing and externalizing problem behavior. The present sample consisted of 216 immigrant Latino youth (43% boys; mean age 13.6 years at baseline; SD = 1.44 years, range 10 to 17). Exploratory structural equation modeling identified factor structures for the BIQ-S and ARSMA-II that diverged from their hypothesized structure. Growth curve models also indicate divergence between the BIQ-S and ARSMA-II in terms of change in acculturation and enculturation processes. Finally, the present findings emphasized that measures of acculturation and enculturation are not equivalent in terms of their effects on internalizing and externalizing problems.
Maturational gene upregulation and mitochondrial activity enhancement in mouse in vitro matured oocytes and using granulosa cell conditioned medium
Authors: Zand Elnaz , Fathi Rouhollah , Nasrabadi Mitra Heydari , Atrabi Mohammad Jafari , Spears Norah , Akbarinejad Vahid
Published: October 2018

The high miscarriage rates that result following transfer of embryos derived from in vitro maturation (IVM) of oocytes necessitate improvements in the processes involved. This study aimed to improve the quality of in vitro matured oocytes using granulosa cell conditioned medium (GCCM) as the culture medium. In this work, germinal vesicle (GV)-stage oocytes from NMRI mice were collected and cultured using three types of culture medium: Base medium (BM) (control), 50% granulosa cell conditioned medium (GCCM50) and 100% GCCM (GCCM100). After IVM, the mitochondria activity potential and viability of metaphase II (MII) oocytes were evaluated by JC-1 and trypan blue staining, respectively. Maturational gene expression levels of CyclinB1, Cdk1 and Gdf9 in the control, GCCM50 and GCCM100 samples were analyzed using real-time polymerase chain reaction (PCR). The viability rate of in vitro matured oocytes was highest in the GCCM50 group. JC-1 staining showed that GCCM50 enhances mitochondrial activity more than the other groups (P < 0.05). Gene expression levels of Cdk1 and Gdf9 were higher in the group with GCCM50 treatment, than in the control and GCCM100 groups (P < 0.05), while the expression level of CyclinB1 did not differ among the groups. The results indicated that a 50% concentration of GCCM in combination with BM components enhanced MII and viability rates and mitochondria activity of mouse immature oocytes.
Le lipœdème, cet inconnu
Authors: Depairon Michèle , Tomson Didier , Lessert Claudia , Mazzolai Lucia
Published: October 2018

Zusammenfassung. Lipödem-Patienten leiden an der weit verbreiteten Unkenntnis ihrer Pathologie. Angesichts ihres chronischen, fortschreitenden und invalidierenden Charakters muss die frühe Diagnose der Krankheit ZIel der Bezugspersonen sein, um medizinische Wanderungen und das Auftreten komplexer Krankheitsbilder zu begrenzen. Behandlungen ermöglichen die Reduzierung von Lipödemen und deren Langzeitkontrolle. Das Management muss entsprechend dem Krankheitsstadium individualisiert werden. Die Compliance des Patienten, die Überwachung und die Unterstützung durch den Arzt sind für das Erreichen der besten Ergebnisse unerlässlich.
Improved Searchability for AGU Content
Authors: Lunn Jenny
Published: October 2018

Staying abreast of the latest research is now easier for AGU readers with a new web platform.
Accounting for Vertical Subgrid‐Scale Heterogeneity in Low‐Level Cloud Fraction Parameterizations
Authors: Jouhaud J. , Dufresne J.‐L. , Madeleine J.‐B. , Hourdin F. , Couvreux F. , Villefranque N. , Jam A.
Published: October 2018

Many general circulation models (GCMs) assume some heterogeneity of water amounts in their grid boxes and use probability density functions to parameterize cloud fractions CF and amounts of condensed water qc. Most GCM cloud schemes calculate the CF as the volume of the grid box that contains clouds (CFvol), whereas radiative fluxes primarily depend on the CF by surface (CFsurf), that is, the surface of the grid box covered by clouds when looking from above. This discrepancy matters as previous findings suggest that CFsurf is typically greater than CFvol by about 30%. In this paper we modify the single column model version of the LMDz GCM cloud scheme by introducing the vertical subgrid‐scale heterogeneity of water content. This allows to distinctly compute the two fractions, CFvol and CFsurf, as well as the amount of condensed water qc. This study is one of the first to take into account such vertical subgrid‐scale heterogeneity in a GCM cloud scheme. Three large eddy simulation cases of cumuliform boundary layer clouds are used to test and calibrate two different parameterizations. These new developments increase cloud cover by about 10% for the oceanic cases RICO and Barbados Oceanographic Meteorological Experiment and by up to 50% for the continental case ARM. The change in condensed water reduces the liquid water path by 10–20% and therefore the cloud opacity by 5–50%. These results show the potential of the new scheme to reduce the too few, too bright bias by increasing low‐level CF and decreasing cloud reflectance.
A subtype of cancer-associated fibroblasts with lower expression of alpha-smooth muscle actin suppresses stemness through BMP4 in oral carcinoma
Authors: Patel Ankit Kumar , Vipparthi Kavya , Thatikonda Venu , Arun Indu , Bhattacharjee Samsiddhi , Sharan Rajeev , Arun Pattatheyil , Singh Sandeep
Published: October 2018

Cancer-associated fibroblasts (CAFs) demonstrate the characteristics of myofibroblast differentiation by often expressing the ultrastructure of alpha-smooth muscle actin (αSMA). However, heterogeneity among cancer-associated fibroblasts (CAFs), with respect to αSMA expression, has been demonstrated in several clinical studies of oral cancer. Like normal stem cells, stem-like cancer cells (SLCCs) are also regulated extrinsically by its microenvironment; therefore, we postulated that the heterogeneous oral-CAFs would differently regulate oral-SLCCs. Using transcriptomics, we clearly demonstrated that the gene expression differences between oral tumor-derived CAFs were indeed the molecular basis of heterogeneity. This also grouped these CAFs in two distinct clusters, which were named as C1 and C2. Interestingly, the oral-CAFs belonging to C1 or C2 clusters showed low or high αSMA-score, respectively. Our data with tumor tissues and in vitro co-culture experiments interestingly demonstrated a negative correlation between αSMA-score and cell proliferation, whereas, the frequency of oral-SLCCs was significantly positively correlated with αSMA-score. The oral-CAF-subtype with lower score for αSMA (C1-type CAFs) was more supportive for cell proliferation but suppressive for the self-renewal growth of oral-SLCCs. Further, we found the determining role of BMP4 in C1-type CAFs-mediated suppression of self-renewal of oral-SLCCs. Overall, we have discovered an unexplored interaction between CAFs with lower-αSMA expression and SLCCs in oral tumors and provided the first evidence about the involvement of CAF-expressed BMP4 in regulation of self-renewal of oral-SLCCs.
Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis
Authors: Chen Xin , Li Wan-Xia , Chen Yu , Li Xiao-Feng , Li Hai-Di , Huang Hui-Min , Bu Fang-Tian , Pan Xue-Yin , Yang Yang , Huang Cheng , Meng Xiao-Ming , Li Jun
Published: October 2018

Hepatic myofibroblasts, activated hepatic stellate cells (HSCs), are the main cell type of extracellular matrix (ECM) deposition during hepatic fibrosis. Aberrant DNA methylation-regulated HSCs activation in liver fibrogenesis has been reported, but the functional roles and mechanisms of DNA methylation in hepatic fibrosis remain to be elucidated. In the present study, reduced representation bisulfite sequencing (RRBS) analysis of primary HSCs revealed hypermethylation patterns in hepatic fibrosis. Interestingly, we found SAD1/UNC84 domain protein-2 (SUN2) gene hypermethylation at CpG sites during liver fibrogenesis in mice with CCl4-induced hepatic fibrosis, which was accompanied by low expression of SUN2. In vivo overexpression of SUN2 following adeno-associated virus-9 (AAV9) administration inhibited CCl4-induced liver injury and reduced fibrogenesis marker expression. Consistently, in vitro experiments showed that enforced expression of SUN2 suppressed HSCs activation and exerted anti-fibrogenesis effects in TGF-β1-activated HSC-T6 cells. In addition, the signaling mechanisms related to SUN2 expression were investigated in vivo and in vitro. Methyltransferase-3b (DNMT3b) is the principal regulator of SUN2 expression. Mechanistically, inhibition of protein kinase B (AKT) phosphorylation may be a crucial pathway for SUN2-mediated HSCs activation. In conclusion, these findings provide substantial new insights into SUN2 in hepatic fibrosis.
Akt2 mediates glucocorticoid resistance in lymphoid malignancies through FoxO3a/Bim axis and serves as a direct target for resistance reversal
Authors: Xie Mixue , Yang Apeng , Ma Jiexian , Wu Min , Xu Hongyue , Wu Kefei , Jin Youxin , Xie Yanhui
Published: October 2018

Glucocorticoids (GCs) are widely used drugs in the treatment of lymphoid malignancies; resistance of GCs in lymphocytes confers poor prognosis and the mechanisms are poorly understood. Here, we found T-acute lymphoblastic leukemia (T-ALL) cells acquire resistance to dexamethasone (DEX)-mediated killing through abnormal activation of Akt, resulting in inhibition of the FoxO3a/Bim pathway. The resistant state was reported to be associated with increased glycolysis, NOTCH1 activating mutations and activated PI3K/ serum GS regulated kinases (SGK) pathway. Use of aforementioned pathway inhibitors blocked FoxO3a-phosphorylation and partially improved DEX-mediated killing of GC-resistant T-ALL cells, further revealing the essential role of the FoxO3a/Bim pathway in the development of GC resistance. Inhibition of Akt is most effective at restoring sensitivity to DEX of GC-resistant lymphocytes in vitro and in vivo, but shows significant hepatotoxicity in vivo. A significantly elevated expression of Akt2 not Akt1 in intrinsically, secondarily GC-resistant lymphocytes and relapsed/refractory ALL patients implicates a more specific target for GC resistance. Mechanistically, Akt2 has a stronger binding capacity with FoxO3a compared to Akt1, and acts as a direct and major negative regulator of FoxO3a activity driving GC resistance. Pharmacologic inhibition of Akt2 more effectively restores sensitivity to GCs than inhibition of Akt1 in vitro, shows higher synergistic effect acting with DEX, and reverses GC resistance in GC-resistant T- or B- lymphoid tumors in vivo with reduced liver toxicity. In summary, these results suggest that Akt2 might serve as a more direct and specific kinase mediating GC resistance through FoxO3a/Bim signaling pathway, and Akt2 inhibition may be explored as a promising target for treating GC-resistant hematopoietic malignancies.
Novel engineered, membrane-localized variants of vascular endothelial growth factor (VEGF) protect retinal ganglion cells: a proof-of-concept study
Authors: Shen Junhui , Xiao Ru , Bair Jeffrey , Wang Fang , Vandenberghe Luk H. , Dartt Darlene , Baranov Petr , Ng Yin Shan Eric
Published: October 2018

Endogenous vascular endothelial growth factor (VEGF-A) can protect retinal ganglion cells (RGC) from stress-induced cell death in ocular hypertensive glaucoma. To exploit the neuroprotective function of VEGF-A for therapeutic application in ocular disorders such as glaucoma while minimizing unwanted vascular side effects, we engineered two novel VEGF variants, eVEGF-38 and eVEGF-53. These variants of the diffusible VEGF-A isoform VEGF121 are expressed as dimeric concatamers and remain tethered to the cell membrane, thus restricting the effects of the engineered VEGF to the cells expressing the protein. For comparison, we tested a Myc-tagged version of VEGF189, an isoform that binds tightly to the extracellular matrix and heparan sulfate proteoglycans at the cell surface, supporting only autocrine and localized juxtacrine signaling. In human retinal endothelial cells (hREC), expression of eVEGF-38, eVEGF-53, or VEGF189 increased VEGFR2 phosphorylation without increasing expression of pro-inflammatory markers, relative to VEGF165 protein and vector controls. AAV2-mediated transduction of eVEGF-38, eVEGF-53, or VEGF189 into primary mouse RGC promoted synaptogenesis and increased the average total length of neurites and axons per RGC by ~ 12-fold, an increase that was mediated by VEGFR2 and PI3K/AKT signaling. Expression of eVEGF-38 in primary RGC enhanced expression of genes associated with neuritogenesis, axon outgrowth, axon guidance, and cell survival. Transduction of primary RGC with any of the membrane-associated VEGF constructs increased survival both under normal culture conditions and in the presence of the cytotoxic chemicals H2O2 (via VEGFR2/PI3K/AKT signaling) and N-methyl-d-aspartate (via reduced Ca2+ influx). Moreover, RGC number was increased in mouse embryonic stem cell-derived retinal organoid cultures transduced with the eVEGF-53 construct. The novel, engineered VEGF variants eVEGF-38 and eVEGF-53 show promise as potential therapeutics for retinal RGC neuroprotection when delivered using a gene therapy approach.
Transient receptor potential channel 6 knockdown prevents apoptosis of renal tubular epithelial cells upon oxidative stress via autophagy activation
Authors: Hou Xin , Xiao Haitao , Zhang Yanhong , Zeng Xixi , Huang Mengjun , Chen Xiaoyun , Birnbaumer Lutz , Liao Yanhong
Published: October 2018

Reactive oxygen species (ROS) are generated under various pathological conditions such as renal ischemia/reperfusion (I/R) injury and provoke damage to multiple cellular organelles and processes. Overproduction of ROS causes oxidative stress and contributes to damages of renal proximal tubular cells (PTC), which are the main cause of the pathogenesis of renal I/R injury. Autophagy is a dynamic process that removes long-lived proteins and damaged organelles via lysosome-mediated degradation, which has an antioxidant effect that relieves oxidative stress. The canonical transient receptor potential channel 6 (TRPC6), a nonselective cation channel that allows passage of Ca2+, plays an important role in renal disease. Yet, the relationship between TRPC6 and autophagy, as well as their functions in renal oxidative stress injury, remains unclear. In this study, we found that oxidative stress triggered TRPC6-dependent Ca2+ influx in PTC to inhibit autophagy, thereby rendering cells more susceptible to death. We also demonstrated that TRPC6 knockout (TRPC6-/-) or inhibition by SAR7334, a TRPC6-selective inhibitor, increased autophagic flux and mitigated oxidative stress-induced apoptosis of PTC. The protective effects of TRPC6 ablation were prevented by autophagy inhibitors Chloroquine and Bafilomycin A1. Moreover, this study also shows that TRPC6 blockage promotes autophagic flux via inhibiting the PI3K/Akt/mTOR and ERK1/2 signaling pathways. This is the first evidence showing that TRPC6-mediated Ca2+ influx plays a novel role in suppressing cytoprotective autophagy triggered by oxidative stress in PTC, and it may become a novel therapeutic target for the treatment of renal oxidative stress injury in the future.
Long noncoding RNA MEG3 regulates LATS2 by promoting the ubiquitination of EZH2 and inhibits proliferation and invasion in gallbladder cancer
Authors: Jin Longyang , Cai Qiang , Wang Shouhua , Wang Shuqing , Mondal Tanmoy , Wang Jiandong , Quan Zhiwei
Published: October 2018

Gallbladder cancer (GBC) is the most common type of biliary tract cancer worldwide. Long noncoding RNAs (lncRNAs) play essential roles in physiological and pathological development. LncRNA MEG3, a tumor suppressor, has been reported to play important roles in some cancers, but the role of MEG3 in GBC remains largely unknown. The purpose of the present study was to explore the role of MEG3 in proliferation and invasion and the potential molecular mechanism in GBC. We found that MEG3 was downregulated in GBC tissues and cells, and low expression of MEG3 was correlated with poor prognostic outcomes in patients. Overexpression of MEG3 inhibited GBC cell proliferation and invasion, induced cell apoptosis and decreased tumorigenicity in nude mice. Moreover, we found that MEG3 was associated with EZH2 and attenuated EZH2 by promoting its ubiquitination. Furthermore, MEG3 executed its functions via EZH2 to regulate the downstream target gene LATS2. Taken together, these findings suggest that MEG3 is an effective target for GBC therapy and may facilitate the development of lncRNA-directed diagnostics and therapeutics against GBC.
A sulfotransferase dosage-dependently regulates mouthpart polyphenism in the nematode Pristionchus pacificus
Authors: Bui Linh T. , Ivers Nicholas A. , Ragsdale Erik J.
Published: October 2018

Polyphenism, the extreme form of developmental plasticity, is the ability of a genotype to produce discrete morphologies matched to alternative environments. Because polyphenism is likely to be under switch-like molecular control, a comparative genetic approach could reveal the molecular targets of plasticity evolution. Here we report that the lineage-specific sulfotransferase SEUD-1, which responds to environmental cues, dosage-dependently regulates polyphenism of mouthparts in the nematode Pristionchus pacificus. SEUD-1 is expressed in cells producing dimorphic morphologies, thereby integrating an intercellular signalling mechanism at its ultimate target. Additionally, multiple alterations of seud-1 support it as a potential target for plasticity evolution. First, a recent duplication of seud-1 in a sister species reveals a direct correlation between genomic dosage and polyphenism threshold. Second, inbreeding to produce divergent polyphenism thresholds resulted in changes in transcriptional dosage of seud-1. Our study thus offers a genetic explanation for how plastic responses evolve.
Maintaining and breaking symmetry in homomeric coiled-coil assemblies
Authors: Rhys Guto G. , Wood Christopher W. , Lang Eric J. M. , Mulholland Adrian J. , Brady R. Leo , Thomson Andrew R. , Woolfson Derek N.
Published: October 2018

In coiled-coil (CC) protein structures α-helices wrap around one another to form rope-like assemblies. Most natural and designed CCs have two–four helices and cyclic (Cn) or dihedral (Dn) symmetry. Increasingly, CCs with five or more helices are being reported. A subset of these higher-order CCs is of interest as they have accessible central channels that can be functionalised; they are α-helical barrels. These extended cavities are surprising given the drive to maximise buried hydrophobic surfaces during protein folding and assembly in water. Here, we show that α-helical barrels can be maintained by the strategic placement of β-branched aliphatic residues lining the lumen. Otherwise, the structures collapse or adjust to give more-complex multi-helix assemblies without Cnor Dnsymmetry. Nonetheless, the structural hallmark of CCs—namely, knobs-into-holes packing of side chains between helices—is maintained leading to classes of CCs hitherto unobserved in nature or accessed by design.
Sequencing HIV-neutralizing antibody exons and introns reveals detailed aspects of lineage maturation
Authors: Johnson Erik L. , Doria-Rose Nicole A. , Gorman Jason , Bhiman Jinal N. , Schramm Chaim A. , Vu Ashley Q. , Law William H. , Zhang Baoshan , Bekker Valerie , Abdool Karim Salim S. , Ippolito Gregory C. , Morris Lynn , Moore Penny L. , Kwong Peter D. , Mascola John R. , Georgiou George
Published: October 2018

The developmental pathways of broadly neutralizing antibodies (bNAbs) against HIV are of great importance for the design of immunogens that can elicit protective responses. Here we show the maturation features of the HIV-neutralizing anti-V1V2 VRC26 lineage by simultaneously sequencing the exon together with the downstream intron of VRC26 members. Using the mutational landscapes of both segments and the selection-free nature of the intron region, we identify multiple events of amino acid mutational convergence in the complementarity-determining region 3 (CDR3) of VRC26 members, and determine potential intermediates with diverse CDR3s to a late stage bNAb from 2 years prior to its isolation. Moreover, we functionally characterize the earliest neutralizing intermediates with critical CDR3 mutations, with some emerging only 14 weeks after initial lineage detection and containing only ~6% V gene mutations. Our results thus underscore the utility of analyzing exons and introns simultaneously for studying antibody maturation and repertoire selection.
Typing tumors using pathways selected by somatic evolution
Authors: Wang Sheng , Ma Jianzhu , Zhang Wei , Shen John Paul , Huang Justin , Peng Jian , Ideker Trey
Published: October 2018

Many recent efforts to analyze cancer genomes involve aggregation of mutations within reference maps of molecular pathways and protein networks. Here, we find these pathway studies are impeded by molecular interactions that are functionally irrelevant to cancer or the patient’s tumor type, as these interactions diminish the contrast of driver pathways relative to individual frequently mutated genes. This problem can be addressed by creating stringent tumor-specific networks of biophysical protein interactions, identified by signatures of epistatic selection during tumor evolution. Using such an evolutionarily selected pathway (ESP) map, we analyze the major cancer genome atlases to derive a hierarchical classification of tumor subtypes linked to characteristic mutated pathways. These pathways are clinically prognostic and predictive, including the TP53-AXIN-ARHGEF17 combination in liver and CYLC2-STK11-STK11IP in lung cancer, which we validate in independent cohorts. This ESP framework substantially improves the definition of cancer pathways and subtypes from tumor genome data.
Haplosaurus computes protein haplotypes for use in precision drug design
Authors: Spooner William , McLaren William , Slidel Timothy , Finch Donna K. , Butler Robin , Campbell Jamie , Eghobamien Laura , Rider David , Kiefer Christine Mione , Robinson Matthew J. , Hardman Colin , Cunningham Fiona , Vaughan Tristan , Flicek Paul , Huntington Catherine Chaillan
Published: October 2018

Selecting the most appropriate protein sequences is critical for precision drug design. Here we describe Haplosaurus, a bioinformatic tool for computation of protein haplotypes. Haplosaurus computes protein haplotypes from pre-existing chromosomally-phased genomic variation data. Integration into the Ensembl resource provides rapid and detailed protein haplotypes retrieval. Using Haplosaurus, we build a database of unique protein haplotypes from the 1000 Genomes dataset reflecting real-world protein sequence variability and their prevalence. For one in seven genes, their most common protein haplotype differs from the reference sequence and a similar number differs on their most common haplotype between human populations. Three case studies show how knowledge of the range of commonly encountered protein forms predicted in populations leads to insights into therapeutic efficacy. Haplosaurus and its associated database is expected to find broad applications in many disciplines using protein sequences and particularly impactful for therapeutics design.
Transformation of amorphous calcium phosphate to bone-like apatite
Authors: Lotsari Antiope , Rajasekharan Anand K. , Halvarsson Mats , Andersson Martin
Published: October 2018

Mineralisation of calcium phosphates in bone has been proposed to proceed via an initial amorphous precursor phase which transforms into nanocrystalline, carbonated hydroxyapatite. While calcium phosphates have been under intense investigation, the exact steps during the crystallisation of spherical amorphous particles to platelet-like bone apatite are unclear. Herein, we demonstrate a detailed transformation mechanism of amorphous calcium phosphate spherical particles to apatite platelet-like crystals, within the confined nanodomains of a bone-inspired nanocomposite. The transformation is initiated under the presence of humidity, where nanocrystalline areas are formed and crystallisation advances via migration of nanometre sized clusters by forming steps at the growth front. We propose that such transformation is a possible crystallisation mechanism and is characteristic of calcium phosphates from a thermodynamic perspective and might be unrelated to the environment. Our observations provide insight into a crucial but unclear stage in bone mineralisation, the origins of the nanostructured, platelet-like bone apatite crystals.
Highly selective transition-metal-free transamidation of amides and amidation of esters at room temperature
Authors: Li Guangchen , Szostak Michal
Published: October 2018

Amide chemistry has an essential role in the synthesis of high value molecules, such as pharmaceuticals, natural products, and fine chemicals. Over the past years, several examples of transamidation reactions have been reported. In general, transition-metal-based catalysts or harsh conditions are employed for these transformations due to unfavorable kinetics and thermodynamics of the process. Herein, we report a significant advance in this area and present the general method for transition-metal-free transamidation of amides and amidation of esters by highly selective acyl cleavage with non-nucleophilic amines at room temperature. In contrast to metal-catalyzed protocols, the method is operationally-simple, environmentally-friendly, and operates under exceedingly mild conditions. The practical value is highlighted by the synthesis of valuable amides in high yields. Considering the key role of amides in various branches of chemical science, we envision that this broadly applicable method will be of great interest in organic synthesis, drug discovery, and biochemistry.
Mediterranean UNESCO World Heritage at risk from coastal flooding and erosion due to sea-level rise
Authors: Reimann Lena , Vafeidis Athanasios T. , Brown Sally , Hinkel Jochen , Tol Richard S. J.
Published: October 2018

UNESCO World Heritage sites (WHS) located in coastal areas are increasingly at risk from coastal hazards due to sea-level rise. In this study, we assess Mediterranean cultural WHS at risk from coastal flooding and erosion under four sea-level rise scenarios until 2100. Based on the analysis of spatially explicit WHS data, we develop an index-based approach that allows for ranking WHS at risk from both coastal hazards. Here we show that of 49 cultural WHS located in low-lying coastal areas of the Mediterranean, 37 are at risk from a 100-year flood and 42 from coastal erosion, already today. Until 2100, flood risk may increase by 50% and erosion risk by 13% across the region, with considerably higher increases at individual WHS. Our results provide a first-order assessment of where adaptation is most urgently needed and can support policymakers in steering local-scale research to devise suitable adaptation strategies for each WHS.
The H3K9 methyltransferase SETDB1 maintains female identity in Drosophila germ cells
Authors: Smolko Anne E. , Shapiro-Kulnane Laura , Salz Helen K.
Published: October 2018

The preservation of germ cell sexual identity is essential for gametogenesis. Here we show that H3K9me3-mediated gene silencing is integral to female fate maintenance in Drosophila germ cells. Germ cell specific loss of the H3K9me3 pathway members, the H3K9 methyltransferase SETDB1, WDE, and HP1a, leads to ectopic expression of genes, many of which are normally expressed in testis. SETDB1 controls the accumulation of H3K9me3 over a subset of these genes without spreading into neighboring loci. At phf7, a regulator of male germ cell sexual fate, the H3K9me3 peak falls over the silenced testis-specific transcription start site. Furthermore, H3K9me3 recruitment to phf7 and repression of testis-specific transcription is dependent on the female sex determination gene Sxl. Thus, female identity is secured by an H3K9me3 epigenetic pathway in which Sxl is the upstream female-specific regulator, SETDB1 is the required chromatin writer, and phf7 is one of the critical SETDB1 target genes.
Publisher Correction: Evidence linking microRNA suppression of essential prosurvival genes with hippocampal cell death after traumatic brain injury
Authors: Boone Deborah Kennedy , Weisz Harris A. , Bi Min , Falduto Michael T. , Torres Karen E. O. , Willey Hannah E. , Volsko Christina M. , Kumar Anjali M. , Micci Maria-Adelaide , Dewitt Douglas S. , Prough Donald S. , Hellmich Helen L.
Published: October 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.