bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of serelaxin when added to standard of care in patients with acute heart failure: results from a PROBE study, RELAX‐AHF‐EU
Authors: Maggioni Aldo P. , López‐Sendón José , Nielsen Olav W. , Hallén Jonas , Aalamian‐Mattheis Maryam , Wang Yaqin , Ertl Georg 
Published: January 2019

AimSerelaxin is a recombinant human relaxin‐2 hormone, which confers receptor‐mediated vasodilatation in a tissue‐specific fashion. The RELAX‐AHF‐EU study assessed the effect of serelaxin when added to standard‐of‐care (SoC) therapy on worsening heart failure (WHF)/all‐cause death through Day 5 in patients hospitalised for acute heart failure (AHF) in Europe.Methods and resultsThis multicentre, prospective, randomised, open‐label, blinded‐endpoint validation study enrolled hospitalised AHF patients and randomised (2:1) eligible patients (mild‐to‐moderate renal impairment and systolic blood pressure ≥ 125 mmHg) within 16 h of presentation with signs/symptoms of AHF, to receive 48 h intravenous infusion of 30 μg/kg/day serelaxin + SoC or SoC alone. The primary endpoint was adjudicated WHF/all‐cause death through Day 5. Of 3183 patients targeted, 2666 were randomised when the study was terminated early by the sponsor due to the neutral results of the pivotal RELAX‐AHF‐2 study. Adjudicated WHF/all‐cause death through Day 5 was significantly reduced in the serelaxin + SoC vs. SoC group (5.0% vs. 6.9%; hazard ratio 0.71; 95% confidence interval 0.51–0.98; P = 0.0172) (absolute risk reduction 1.9%, number needed to treat 53). The difference between treatment groups was not significant for WHF/all‐cause death/heart failure rehospitalisation through Day 14 and length of hospital stay. A significantly smaller proportion of patients in the serelaxin + SoC vs. SoC group experienced persistent heart failure signs/symptoms at each visit until Day 4, or renal deterioration through Day 5 (all P ≤ 0.01). Overall incidence of treatment‐emergent adverse events was comparable between treatment groups. Hypotension and decrease in haemoglobin/haematocrit were more frequent in the serelaxin + SoC group.ConclusionWhen added to SoC, serelaxin reduced adjudicated WHF or all‐cause death through Day 5 in AHF patients. The results from this open‐label study should be considered in the context of the totality of the double‐blind, randomised evidence on serelaxin in AHF.
Institutional quality and sovereign credit default swap spreads
Authors: Huang Wei , Lin Shu , Yang Jian 
Published: January 2019

AbstractWe examine how the quality of political, legal, and regulatory institutions impacts sovereign risk premia. An improvement in institutional quality significantly lowers a country's sovereign credit default swap (CDS) spread, even after controlling for domestic and global macroeconomic factors. The incremental effect of institutional quality may also be economically important in explaining the variations in the level of sovereign CDS spreads. The basic results are robust to alternative model specifications, samples, control variables, measures of institutional quality, estimation methods, and controls for endogeneity. Overall, the evidence suggests that institutional quality may play a significant role in explaining sovereign CDS spreads.
A review of kernel methods for genetic association studies
Authors: Larson Nicholas B. , Chen Jun , Schaid Daniel J. 
Published: January 2019

ABSTRACTEvaluating the association of multiple genetic variants with a trait of interest by use of kernel‐based methods has made a significant impact on how genetic association analyses are conducted. An advantage of kernel methods is that they tend to be robust when the genetic variants have effects that are a mixture of positive and negative effects, as well as when there is a small fraction of causal variants. Another advantage is that kernel methods fit within the framework of mixed models, providing flexible ways to adjust for additional covariates that influence traits. Herein, we review the basic ideas behind the use of kernel methods for genetic association analysis as well as recent methodological advancements for different types of traits, multivariate traits, pedigree data, and longitudinal data. Finally, we discuss opportunities for future research.
Where is the “where” in the brain? A meta‐analysis of neuroimaging studies on spatial cognition
Authors: Cona Giorgia , Scarpazza Cristina 
Published: January 2019

AbstractSpatial representations are processed in the service of several different cognitive functions. The present study capitalizes on the Activation Likelihood Estimation (ALE) method of meta‐analysis to identify: (a) the shared neural activations among spatial functions to reveal the “core” network of spatial processing; (b) the specific neural activations associated with each of these functions. Following PRISMA guidelines, a total of 133 fMRI and PET studies were included in the meta‐analysis. The overall analysis showed that the core network of spatial processing comprises regions that are symmetrically distributed on both hemispheres and that include dorsal frontoparietal regions, presupplementary motor area, anterior insula, and frontal operculum. The specific analyses revealed the brain regions that are selectively recruited for each spatial function, such as the right temporoparietal junction for shift of spatial attention, the right parahippocampal gyrus, and the retrosplenial cortex for navigation and spatial long‐term memory. The findings are integrated within a systematic review of the neuroimaging literature and a new neurocognitive model of spatial cognition is proposed.
MVA E2 therapeutic vaccine for marked reduction in likelihood of recurrence of respiratory papillomatosis
Authors: Cabo Beltran Olga Rodriguez , Rosales Ledezma Ricardo 
Published: January 2019

AbstractBackgroundRecurrent respiratory papillomatosis (RRP) or laryngeal papillomatosis is a disease caused by papillomavirus infection.MethodsIn this phase I/II clinical trial, we evaluated the efficacy of the modified vaccinia Ankara (MVA) E2 virus in the treatment of RRP. Twenty‐nine patients (18 female and 11 male) underwent injection of MVA E2 directly into the borders of the vocal cords where lesions were seen and were monitored by direct laryngoscopy. The immune response was assessed by the determination of CD3+, CD4+, and CD8+ lymphocytes counts. The presence of papillomavirus was determined by polymerase chain reaction analysis.ResultsLesions were completely eliminated in 13 patients (44.8%). In 16 patients (55.2%), lesions recurred between 6 and 18 months after treatment; these patients received a second round of treatment with MVA E2, and they are not seen with new recurrences.ConclusionThe MVA E2 vaccine has excellent potential for generating complete regression of RRP lesions.
The affective basis of violence
Authors: Mizen Richard 
Published: January 2019

ABSTRACTViolence is a complex matter, and understandingly perhaps, it is the objective, behavioral aspects that are commonly focused on. Here, however, it is the subjective psychological and especially affective substrates of violence that are brought to the fore. Psychoanalytic perspectives provide a way of thinking about these that also sets them in a human‐developmental context. In this essay, psychoanalytic ideas about aggression and violence are considered, and what they have to say about the relationship between states of mind and behavior is critically reviewed. There also is an exploration of the ways that some recent findings in developmental science and neuroscience can refine and augment an understanding of these relationships, facilitating the construction of a psychobiological model, which may be placed in a social context. From this biopsychosocial perspective, aggression is seen as a heuristic concept that encapsulates numerous interacting elements that in ordinary development integrate and serve to promote optimal organism survival: By contrast, from this perspective, in humans violence may be understood as a pathological variant of aggression.
Lead exposure and child maltreatment as models for how to conceptualize early‐in‐life risk factors for violence
Authors: Jaffee Sara R. 
Published: January 2019

ABSTRACTAlthough rates of violent crime have been on the decline in the United States for the past two decades, young people—and particularly young men—continue to commit and fall victim to alarmingly high rates of violence. Effective prevention requires data on what the determinants of violence are and when in the life course they emerge. The goal of this review was to identify early‐in‐life risk factors for violence and to describe (a) who is most affected and (b) effect mechanisms. I focus on abuse and neglect and exposure to lead as risk factors for violence that disproportionately affect young children and that are likely to have causal effects on development. I conclude with future directions for research and intervention.
Manipulating the Amount and Structure of the Organic Matrix Affects the Water Compartments of Human Cortical Bone
Authors: Nyman Jeffry S , Uppuganti Sasidhar , Unal Mustafa , Leverant Calen J , Adabala Saahit , Granke Mathilde , Voziyan Paul , Does Mark D 
Published: January 2019

AbstractBeing predictors of the mechanical properties of human cortical bone, bound and pore water measurements by magnetic resonance (MR) imaging are being developed for the clinical assessment of fracture risk. While pore water is a surrogate of cortical bone porosity, the determinants of bound water are unknown. Manipulation of organic matrix properties by oxidative deproteinization, thermal denaturation, or nonenzymatic glycation lowers bone toughness. Because bound water contributes to bone toughness, we hypothesized that each of these matrix manipulations affect bound water fraction (Vbw/Vbone). Immersing cadaveric bone samples in sodium hypochlorite (NaClO) for 96 hours did not affect tissue mineral density or cortical porosity, but rather decreased Vbw/Vbone and increased short‐T2 pore water signals as determined by 1H nuclear MR relaxometry (1H NMR). Moreover, the post treatment Vbw/Vbone linearly correlated with the remaining weight fraction of the organic matrix. Heating bone samples at 110°C, 120°C, 130°C, and then 140°C (∼24 hours per temperature and rehydration for ∼24 hours before 1H NMR analysis) did not affect Vbw/Vbone. After subsequently heating them at 200°C, Vbw/Vbone increased. Boiling bone samples followed by heating at 110°C, 120°C, and then 130°C in water under pressure (8 hours per temperature) had a similar effect on Vbw/Vbone. Raman spectroscopy analysis confirmed that the increase in Vbw/Vbone coincided with an increase in an Amide I subpeak ratio that is sensitive to changes in the helical structure of collagen I. Glycation of bone by ribose for 4 weeks, but not in glucose for 16 weeks, decreased Vbw/Vbone, although the effect was less pronounced than that of oxidative deproteinization or thermal denaturation. We propose that MR measurements of bound water reflect the amount of bone organic matrix and can be modulated by collagen I helicity and by sugar‐derived post translational modifications of the matrix. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Interaction between caspase‐3 and caspase‐5 in the stretch‐induced programmed cell death in the human periodontal ligament cells
Authors: Wu Yaqin , Zhuang Jiabao , Zhao Dan , Xu Chun 
Published: January 2019

AbstractIn our previous studies, programmed cell death (PCD) was induced in human periodontal ligament (PDL) cells, through activation of caspase‐3 and upregulation of CASP5 gene (encoding caspase‐5 protein), in response to mechanical stretch loading. The aim of this study is to explore the relationship between the inflammatory caspase, caspase‐5, and the apoptotic executioner protein, caspase‐3, in human PDL cells. Here, we found that cyclic stretching upregulated the activity and the protein expression level of caspase‐3 and ‐5 and the addition of the caspase‐3 inhibitor or caspase‐5 inhibitor significantly inhibited the stretch‐induced PCD. Meanwhile, the inhibition of caspase‐5 inhibited the activation of caspase‐3 and vice versa. The result of coimmunoprecipitation also demonstrated that the expression of caspase‐3 was immunoprecipitated with caspase‐5. Thus, our study revealed that the in vitro application of cyclic stretching induced PCD by activation of caspase‐3 and ‐5 in human PDL cells, and these two caspases could interact with each other after mechanical stretch loading. The study may facilitate further studies on the mechanism of stretch‐induced PCD and help us understand the force‐related periodontal homeostasis and remodeling better.
The long noncoding RNA XIST regulates cardiac hypertrophy by targeting miR‐101
Authors: Xiao Lili , Gu Yulei , Sun Yunlong , Chen Jun , Wang Xiaofang , Zhang Yanzhou , Gao Lu , Li Ling 
Published: January 2019

AbstractCardiac hypertrophy and its resultant heart failure are among the most common causes of mortality, worldwide. Long noncoding RNAs (lncRNAs) are involved in diverse biological processes, and their vital role in the regulation of cardiac hypertrophy is increasingly being discovered. Nevertheless, the biological roles of lncRNA X‐inactive specific transcript (XIST) in cardiac hypertrophy are scarcely reported, and the current study was designed to determine whether cardiac hypertrophy can be regulated by XIST and to elucidate the related mechanism. The animals were randomized to receive either an adeno‐associated virus expressing XIST or control plasmid via a single bolus‐tail vein injection. Two weeks later, hypertrophy was established by transverse aortic constriction (TAC) surgery. In vitro, H9c2 cells were used to explore the potential molecular mechanism of XIST in the regulation of phenylephrine (PE)‐induced cardiomyocyte hypertrophy. A luciferase reporter assay and RNA immunoprecipitation were performed to explore the relationships among XIST, microRNA (miR)‐101, and toll‐like receptor 2 (TLR2). In this study, we demonstrated that the expression of XIST was significantly upregulated in hypertrophic mouse hearts and PE‐treated cardiomyocytes. Then, we observed that knockdown of XIST attenuated PE‐induced cardiomyocyte hypertrophy. Conversely, overexpression of XIST aggravated TAC‐induced cardiac hypertrophy. Finally, we demonstrated that miR‐101 was a direct target of XIST, whereas TLR2 was a target of miR‐101. Rescue assays further confirmed that XIST promoted the progression of cardiac hypertrophy through competitively binding with miR‐101 to enhance the expression of TLR2. Collectively, these in vivo and in vitro findings identify XIST as a necessary regulator of cardiac hypertrophy due to its regulation of the miR‐101/TLR2 axis, suggesting that XIST might act as a therapeutic target for the treatment of cardiac hypertrophy and heart failure.
MicroRNA replacement therapy in cancer
Authors: Mollaei Homa , Safaralizadeh Reza , Rostami Zeinab 
Published: January 2019

AbstractDespite the recent progress in cancer management approaches, the mortality rate of cancer is still growing and there are lots of challenges in the clinics in terms of novel therapeutics. MicroRNAs (miRNA) are regulatory small noncoding RNAs and are already confirmed to have a great role in regulating gene expression level by targeting multiple molecules that affect cell physiology and disease development. Recently, miRNAs have been introduced as promising therapeutic targets for cancer treatment. Regulatory potential of tumor suppressor miRNAs, which enables regulation of entire signaling networks within the cells, makes them an interesting option for developing cancer therapeutics. In this regard, over recent decades, scientists have aimed at developing powerful and safe targeting approaches to restore these suppressive miRNAs in cancerous cells.The present review summarizes the function of miRNAs in tumor development and presents recent findings on how miRNAs have served as therapeutic agents against cancer, with a special focus on tumor suppressor miRNAs (mimics). Moreover, the latest investigations on the therapeutic strategies of miRNA delivery have been presented.
Prognostic scoring system for osteosarcoma using network‐regularized high‐dimensional Cox‐regression analysis and potential therapeutic targets
Authors: Goh Tae Sik , Lee Jung Sub , Il Kim Jeung , Park Yong Geon , Pak Kyoungjune , Jeong Dae Cheon , Oh Sae‐Ock , Kim Yun Hak 
Published: January 2019

AbstractWith the recent emphasis on the importance of personalized genomic medicine, studies have performed prognostic stratification using gene signatures in cancers. However, these studies have not considered gene networks with clinical data. Therefore, this study aimed to develop a novel prognostic score using grouped variable selection for patients with osteosarcoma. We assessed messenger RNA (mRNA) expression and clinical data from Gene Expression Omnibus to develop a novel prognostic scoring system for patients with osteosarcoma. Variable selection using Network‐Regularized high‐dimensional Cox‐regression analysis with information regarding gene networks obtained from six large pathway databases was performed. We determined the risk score on the linear combination of regression coefficients and mRNA expression values. Log‐rank test, UNO's c‐index, and area under the curve (AUC) values were determined to evaluate the discriminatory power between the low‐ and high‐risk groups. A recently reported next‐generation Connectivity Map was used to identify future therapeutic targets for osteosarcoma. Our novel model had significantly high discriminatory power in predicting overall survival. An optimal c‐index of 0.967 was obtained and time‐dependent receiver operating characteristic analysis revealed an acceptable predictive value of AUC between 0.953 and 1.000. Knockdown of BACE2 or ING2 and linifanib treatment may improve the prognosis of patients with osteosarcoma. Herein, this novel prognostic scoring system would not only facilitate a more accurate prediction of patient prognosis, but also contribute to the selection of suitable therapeutic alternatives for osteosarcoma patients.
Intraovarian injection of miR‐224 as a marker of polycystic ovarian syndrome declines oocyte competency and embryo development
Authors: Vahdat‐Lasemi Maryam , Hosseini Sara , Jajarmi Vahid , Kazemi Bahram , Salehi Mohammad 
Published: January 2019

AbstractmiR‐224 is associated with polycystic ovary syndrome (PCOS) that is an epidemic in reproductive age women. Most studies of miR‐224 have focused on in vitro analyses, whereas the in vivo effects are not widely understood. In this study, we have conducted in silico analysis and found two potential miR‐224 target genes, Ptx3 and Smad4 that have roles in folliculogenesis. Because patients with PCOS have decreased numbers of follicular cells related to cell apoptosis, we also investigated two apoptotic genes, Bax and Bcl2. We used the intraovarian injection method to deliver miR‐224 into a mouse model. Histological examination of the ovaries was done by fluorescent microscope. Fertilization, cleavage, and developmental competence rates were counted under a stereomicroscope and compared between the studied groups. Quantitative real‐time polymerase chain reaction (qRT‐PCR) analysis of miR‐224 was conducted to determine the levels of the studied genes in the oocytes, cumulus cells, and blastocysts. The numbers of oocytes and fertilization rate indicated a higher apoptosis index (
p < 0.05) and increased numbers of degenerated embryos with irregular blastomeres and fragmented cytoplasm in the experimental group. RT‐PCR results indicated a significant increase in miR‐224 levels in the manipulated group. Of the four analyzed genes, Ptx3, Smad4, and Bcl2 had decreased levels in the transfected group, with increased Bax expression (
p < 0.05). This data showed that miR‐224 negatively affected ovulation in the mouse model by decreasing Ptx3 and Smad4 expressions. The changes in Bcl2 and Bax expression levels, as apoptosis biomarkers, showed that apoptosis was a secondary outcome of the effect of miR‐224.
Train‐the‐trainer: Methodology to learn the cognitive interview
Authors: Molinaro Peter F. , Fisher Ronald P. , Mosser Alexandra E. , Satin Geri E. 
Published: January 2019

AbstractResearch has indicated that police may not receive enough training in interviewing cooperative witnesses, specifically in use of the cognitive interview (CI). Practically, for the CI to be effective in real‐world investigations, police investigators must be trained by law enforcement trainers. We conducted a three‐phase experiment to examine the feasibility of training experienced law enforcement trainers who would then train others to conduct the CI. We instructed Federal Bureau of Investigation and local law enforcement trainers about the CI (Phase I); law enforcement trainers from both agencies (n = 4, 100% male, mean age = 50 years) instructed university students (n = 25, 59% female, mean age = 21 years) to conduct either the CI or a standard law enforcement interview (Phase II); the student interviewers then interviewed other student witnesses (n = 50, 73% female, mean age = 22 years), who had watched a simulated crime (phase III). Compared with standard training, interviews conducted by those trained by CI‐trained instructors contained more information and at a higher accuracy rate and with fewer suggestive questions.
Sirtuin-1 in immunotherapy: A Janus-headed target
Authors: Chadha Sakshum , Wang Liqing , Hancock Wayne W , Beier Ulf H 
Published: January 2019

Abstract
Sirtuin-1 (Sirt1), a member of the NAD-dependent sirtuin family of histone/protein deacetylases (HDAC), is an important target for immunotherapy due to its role in deacetylating the transcription factors Foxp3 and thymic retinoid acid receptor related orphan receptor gamma (RORγt). Sirt1 inhibition can increase Foxp3 acetylation and promote the production and functions of Foxp3+ T-regulatory (Treg) cells, whereas the acetylation of RORγt decreases its transcriptional activity DNA binding and decreases the differentiation of proinflammatory Th17 cells. Pharmacologic inhibitors of Sirt1 increase allograft survival and decrease autoimmune colitis and experimental allergic encephalomyelitis. However, in contrast to its role in T cells, Sirt1 has anti-inflammatory effects in myeloid cells, and, context dependent, in Th17 cells. Here, inhibition of Sirt1 can have proinflammatory effects. In addition to effects arising from the central role of Sirt1 in cellular metabolism and NAD-dependent reactions, such proinflammatory effects further complicate the potential of Sirt1 for therapeutic immunosuppression. This review aims to reconcile the opposing literature on pro- and anti-inflammatory effects of Sirt1, provides an overview of the role of Sir1 in the immune system, and discusses the pros and cons associated with inhibiting Sirt1 for control of inflammation and immune responses.