bluuebunny/crossref_metadata_2025_split huggingface dataset:
An in vivo role for Rho kinase activation in the tumour vascular disrupting activity of combretastatin A‐4 3‐O‐phosphate
Authors: Williams L J , Mukherjee D , Fisher M , Reyes‐Aldasoro C C , Akerman S , Kanthou C , Tozer G M 
Published: June 2014

Background and PurposeCombretastatin A‐4 3‐O‐phosphate (CA4P) is in clinical trial as a tumour vascular disrupting agent (VDA) but the cause of blood flow disruption is unclear. We tested the hypothesis that activation of Rho/Rho kinase (ROCK) is fundamental to the effects of this drug in vivo.Experimental ApproachMouse models of human colorectal carcinoma (SW1222 and LS174T) were used. Effects of the ROCK inhibitor, Y27632, alone or in combination with CA4P, on ROCK activity, vascular function, necrosis and immune cell infiltration in solid tumours were determined. Mean arterial BP (MABP) was measured to monitor systemic interactions and the vasodilator, hydralazine, was used to control for the hypotensive effects of Y27632.Key ResultsY27632 caused a rapid drop in blood flow in SW1222 tumours, with recovery by around 3 h, which was paralleled by MABP changes. Y27632 pretreatment reduced CA4P‐induced ROCK activation and partially blocked CA4P‐induced tumour vascular effects, in both tumour types. Y27632 also partially inhibited CA4P‐induced tumour necrosis and was associated with reduced immune cell infiltration in SW1222 tumours. Hydralazine caused a similar hypotensive effect as Y27632 but had no protective effect against CA4P treatment.Conclusions and ImplicationsThese results demonstrate that ROCK activity is critical for full manifestation of the vascular activity of CA4P in vivo, providing the evidence for pharmacological intervention to enhance the anti‐tumour efficacy of CA4P and related VDAs.
Small‐molecule modulators of the OX40–OX40 ligand co‐stimulatory protein–protein interaction
Authors: Song Yun , Margolles‐Clark Emilio , Bayer Allison , Buchwald Peter 
Published: June 2014

Background and PurposeThe OX40–OX40L protein–protein interaction (PPI) is an important cell‐surface signalling co‐stimulatory regulator within the TNFR superfamily (TNFRSF) and a promising therapeutic target for immunomodulation. PPIs are difficult to modulate using small‐molecules. Here, we describe the identification of a small‐molecule OX40 modulator and confirm its partial agonist character.Experimental ApproachCell‐free screening assays were developed and used to identify OX40–OX40L inhibitors. Modified versions of this assay were used to elucidate the binding partner and the binding nature of active compounds. OX40‐transfected sensor cells with NF‐κB reporters were constructed and used to confirm and characterize activity and specificity. Immunomodulatory activity and partial agonist nature were further confirmed by ex vivo T‐cell polarization assays.Key ResultsSeveral compounds that concentration‐dependently affected OX40‐OX40L were identified. Cell assays indicated that they were partial agonists with low micromolar potency and adequate selectivity. Under polarizing conditions based on TGF‐β, the most promising compound mimicked the effect of an agonistic anti‐OX40 antibody in suppressing regulatory T‐cell generation and diverting CD4+CD62L+Foxp3− cells to TH9 phenotype in vitro.Conclusions and ImplicationsWe identified, to our knowledge, the first small‐molecule compounds able to interfere with OX40–OX40L binding and, more importantly, to act as partial agonists of OX40. This is particularly interesting, as small‐molecule agonism or activation of PPIs is considered unusually challenging and there are only few known examples. These results provide proof‐of‐principle evidence for the feasibility of small‐molecule modulation of the OX40–OX40L interaction and for the existence of partial agonists for TNFRSF‐PPIs.
Navigating family roles and relationships: system youth in the transition years
Authors: Lee Bethany R. , Cole Andrea R. , Munson Michelle R. 
Published: June 2014

AbstractDuring young adulthood, many transitions occur in family relationships. This paper explores family roles for young adults in the transition years who have been in the custody of the child welfare system and have mood challenges. To capture the voices of this less studied subpopulation, we conducted in‐depth qualitative interviews with 44 young adults in a Midwestern state. Through coding interview transcripts, we identified how these young people defined family and issues they were navigating in family relationships. These young people were commonly resolving family history issues especially related to ambiguous and actual losses, as well as the legacy of this history in their present‐day family relationships. Professionals who intervene with this population should be prepared to help young people as they navigate these family transitions and change the future by rewriting family narratives.
Disease‐Modifying Anti‐Alzheimer's Drugs: Inhibitors of Human Cholinesterases Interfering with β‐Amyloid Aggregation
Authors: Brogi Simone , Butini Stefania , Maramai Samuele , Colombo Raffaella , Verga Laura , Lanni Cristina , De Lorenzi Ersilia , Lamponi Stefania , Andreassi Marco , Bartolini Manuela , Andrisano Vincenza , Novellino Ettore , Campiani Giuseppe , Brindisi Margherita , Gemma Sandra 
Published: June 2014

SummaryAimsWe recently described multifunctional tools (2a–c) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with Aβ aggregation. We herein propose a thorough biological and computational analysis aiming at understanding their mechanism of action at the molecular level.MethodsWe determined the inhibitory potency of 2a–c on Aβ1–42 self‐aggregation, the interference of 2a with the toxic Aβ oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of Aβ toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with Aβ and with the Aβ‐preformed fibrils were computationally analyzed. 2a–c toxicity profile was also assessed (human hepatocytes and mouse fibroblasts).ResultsOur prototypical pluripotent analogue 2a interferes with Aβ oligomerization process thus reducing Aβ oligomers‐mediated toxicity in human neuroblastoma cells. 2a also disrupts preformed fibrils. Computational studies highlighted the bases governing the diversified activities of 2a.ConclusionConverging analytical, biological, and in silico data explained the mechanism of action of 2a on Aβ1–42 oligomers formation and against Aβ‐preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues.
Nuclear and mitochondrial genetic structure in the Eurasian beaver (Castor fiber) – implications for future reintroductions
Authors: Senn Helen , Ogden Rob , Frosch Christiane , Syrůčková Alena , Campbell‐Palmer Roisin , Munclinger Pavel , Durka Walter , Kraus Robert H. S. , Saveljev Alexander P. , Nowak Carsten , Stubbe Annegret , Stubbe Michael , Michaux Johan , Lavrov Vladimir , Samiya Ravchig , Ulevicius Alius , Rosell Frank 
Published: June 2014

AbstractMany reintroduction projects for conservation fail, and there are a large number of factors that may contribute to failure. Genetic analysis can be used to help stack the odds of a reintroduction in favour of success, by conducting assessment of source populations to evaluate the possibility of inbreeding and outbreeding depression and by conducting postrelease monitoring. In this study, we use a panel of 306 SNP (single nucleotide polymorphism) markers and 487–489 base pairs of mitochondrial DNA control region sequence data to examine 321 individuals from possible source populations of the Eurasian beaver for a reintroduction to Scotland. We use this information to reassess the phylogenetic history of the Eurasian beavers, to examine the genetic legacy of past reintroductions on the Eurasian landmass and to assess the future power of the genetic markers to conduct ongoing monitoring via parentage analysis and individual identification. We demonstrate the capacity of medium density genetic data (hundreds of SNPs) to provide information suitable for applied conservation and discuss the difficulty of balancing the need for high genetic diversity against phylogenetic best fit when choosing source population(s) for reintroduction.
Social networks and immigration stress among first‐generation Mandarin‐speaking Chinese immigrants in Los Angeles
Authors: Li Yawen , Hofstetter C. Richard , Wahlgren Dennis , Irvin Veronica , Chhay Doug , Hovell Melbourne F. 
Published: June 2014

This study examined relationships between social networks and immigration stress among first‐generation Chinese immigrants. Using data from a larger study of health behavior among first‐generation Mandarin/English‐speaking immigrants residing in the Los Angeles metropolitan area (N = 1,183), this study found that Chinese immigrants living closer to immediate family and maintaining larger social networks experienced lower immigration stress. Unexpectedly, immigrants with larger family sizes and who participated in voluntary associations (e.g., religious, alumni, and nationality associations) reported increased immigration stress. The findings suggest that practitioners need to be cautious of a possible downside in designing interventions to expand social networks among immigrant clients. The study is especially important in the context of a rapidly increasing immigrant population from Mainland China to the USA.Key Practitioner Message: ● Working with immigration families should incorporate assessment of their social network; ● Interventions designed to facilitate supportive social networks should differentiate different social network ties; ● Different social network ties may affect the stress level of immigrants differently.
Oxidation of ZrB2 Nanoparticles at High Temperature under Low Oxygen Pressure
Authors: Zhao Guanghui , Zhang Xinghong , Shen Zhenju , Zhang Dejiong , Hong Changqing , Li Jixue , Zhang Ze 
Published: June 2014

The oxidation of ZrB2 nanoparticles was observed at high temperature of 1500°C under low oxygen partial pressure of 5 × 10−2 Pa by an environmental transmission electron microscope. The results demonstrate that the oxidation starts on the surface of ZrB2 nanoparticles with decomposition of ZrB2 into ZrO2 and B2O3. The nucleation and growth of ZrO2 on the surface of ZrB2 proceed with B2O3 being evaporated.
Interventions for Family Members of Adolescents With Disruptive Behavior Disorders
Authors: Oruche Ukamaka M. , Draucker Claire , Alkhattab Halima , Knopf Amy , Mazurcyk Jill 
Published: June 2014

ProblemThe family members of adolescents diagnosed with disruptive behavior disorders (DBDs) experience profound stress and burden. Despite the need for empirically supported interventions that address the challenges faced by these family members, few such interventions are available.MethodsIn this qualitative descriptive study, we conducted in‐depth interviews with 15 families of adolescents diagnosed with DBD. We asked the family members to identify what types of mental health services they needed and to describe the “ideal” program that would best address their concerns.FindingsFamily members identified several intervention modalities that would fit their needs, including multifamily groups, family therapy, individual therapy, and community‐based hotlines. They indicated that programs should address the following topics: family communication, conflict resolution, education about DBD, and strategies to improve interactions with child service agencies.ConclusionsClinicians should recognize that all family members may need support to manage the stressors associated with caring for or living with adolescents with DBD. When working with families, clinicians should provide information about the etiology and management of DBD, help navigate interactions with child service agencies, and employ strategies to improve family communication and functioning.
“Missing Pieces”—Functional, Social, and Environmental Barriers to Recovery for Vulnerable Older Adults Transitioning from Hospital to Home
Authors: Greysen S. Ryan , Hoi‐Cheung Doug , Garcia Veronica , Kessell Eric , Sarkar Urmimala , Goldman Lauren , Schneidermann Michelle , Critchfield Jeffrey , Pierluissi Edgar , Kushel Margot 
Published: June 2014

ObjectivesTo describe barriers to recovery at home for vulnerable older adults after leaving the hospital.DesignStandard qualitative research techniques, including purposeful sampling of participants according to age, sex, race, and English proficiency, were used to ensure a wide breadth of experiences. All participants were interviewed in their native language (English, Spanish, or Chinese). Two investigators independently coded interviews using the constant comparative method. The entire research team, with diverse backgrounds in primary care, hospital medicine, geriatrics, and nursing, performed thematic analysis.SettingUrban public safety‐net teaching hospital.ParticipantsVulnerable older adults (low income and health literacy, limited English proficiency) enrolled in a larger discharge interventional study.MeasurementsQualitative data (participant quotations) were organized into themes.ResultsTwenty‐four individuals with a mean age of 63 (range 55–84), 66% male, 67% nonwhite, 16% Spanish speaking, 16% Chinese speaking were interviewed. An overarching theme of “missing pieces” was identified in the plan for postdischarge recovery at home, from which three specific subthemes emerged: functional limitations and difficulty with mobility and self‐care tasks, social isolation and lack of support from family and friends, and challenges from poverty and the built environment at home. In contrast, participants described mostly supportive experiences with traditional focuses of transition, care such as following prescribed medication and diet regimens.ConclusionHospital‐based discharge interventions that focus on traditional aspects of care may overlook social and functional gaps in postdischarge care at home for vulnerable older adults. Postdischarge interventions that address these challenges may be necessary to reduce readmissions in this population.
Generating anatomical variation through mutations in networks – implications for evolution
Authors: Bard Jonathan 
Published: June 2014

AbstractGenetic mutation leads to anatomical variation only indirectly because many proteins involved in generating anatomical structures in embryos operate cooperatively within molecular networks. These include gene‐regulatory or control networks (CNs) for timing, signaling and patterning together with the process networks (PNs) for proliferation, apoptosis, differentiation and morphogenesis that they control. This paper argues that anatomical variation is achieved through a two‐stage process: mutation alters the outputs of CNs and perhaps the proliferation network, and such changed outputs alter the ways that PNs construct tissues. This systems‐biology approach has several implications: first, because networks contain many cooperating proteins, they amplify the effects of genetic variation so enabling mutation to generate a wider range of phenotypes than a single changed protein acting alone could. Second, this amplification helps explain how novel phenotypes can be produced relatively rapidly. Third, because even organisms with novel anatomical phenotypes derive from variants in standard networks, there is no genetic barrier to their producing viable offspring. This approach also clarifies a terminological difficulty: classical evolutionary genetics views genes in terms of phenotype heritability rather than as DNA sequences. This paper suggests that the molecular phenotype of the classical concept of a gene is often a protein network, with a mutation leading to an alteration in that network's dynamics.
IL‐18 gene polymorphisms in aphthous stomatitis vs. Behçet's disease in a cohort of Egyptian patients
Authors: Hazzaa Hala H. A. , Rashwan Weam A. M. , Attia Enas A. S. 
Published: June 2014

ObjectiveA clinical investigation of the potential correlation of two single‐nucleotide polymorphisms at −137 (G/C) and −607 (C/A) in the promoter region of the IL‐18 gene, with the susceptibility to aphthous stomatitis and Behçet's disease.Patient and MethodsThis study included 80 aphthous stomatitis patients and 80 patients with Behçet's disease. Eighty healthy subjects were enrolled as a control group. IL‐18 single‐nucleotide polymorphisms at −607 and −137 regions were analyzed using polymerase chain reaction–restriction fragment length polymorphism analysis.ResultsThe genotype and allele distributions of the two regions did not differ significantly between patients with aphthous stomatitis and controls. The genotype and allele distributions at −607 were significantly different between patients with Behçet's disease [CC (P = 0.044), C allele (P = 0.043), A allele (P = 0.043)], and controls. The frequency of the GG genotype at position −137 in patients with Behçet's disease was associated only with a higher rate of ocular manifestations (OR= 1.4, CI= 0.76–2.7, P = 0.031).ConclusionIL‐18 gene polymorphisms were not associated with any susceptibility to aphthous stomatitis, while a positive association was found with patients with Behçet's disease regarding −607 promoter site. Moreover, patients with Behçet's disease carrying the GG genotype at position −137 had a higher risk of developing ocular manifestations.
Histomorphometry in antigen‐induced arthritis of the rabbit temporomandibular joint
Authors: Rafayelyan S. , Radlanski R. J. , Minden K. , Pischon N. , Jost‐Brinkmann P.‐G. , Präger T. M. 
Published: June 2014

BackgroundJuvenile idiopathic arthritis (JIA) of the temporomandibular joint (TMJ) can cause severe growth disturbances of the craniomandibular system. Antigen‐induced arthritis (AIA) of the rabbit TMJ is simulating the inflammatory process of the TMJ in JIA. The aim of this study was to investigate the effect of a systemic administration of the tumor necrosis factor‐alpha (TNF‐α) antagonist etanercept on AIA in rabbits by means of three different histological staining methods.MethodsAfter sensitization, a bilateral arthritis of the TMJ was induced and maintained by repeated intra‐articular administrations of ovalbumin in 12 New Zealand white rabbits aged 10 weeks. From the 13th week of age, 6 of the 12 rabbits received weekly subcutaneous injections of etanercept, and the other 6 animals remained without therapy. Another 6 animals served as controls, receiving no treatment or intra‐articular injections at all. After euthanasia at the age of 22 weeks, all TMJs were retrieved en bloc. Sagittal sections were cut and stained with hematoxylin–eosin (H‐E), Safranin‐O for the evaluation of the Mankin score, and tartrate‐resistant acid phosphatase (TRAP).ResultsIn the arthritis group, a chronic inflammation with degeneration of the articular cartilage was visible. In the etanercept group, the signs of cartilage degeneration were significantly reduced but present. In contrast, the joints in the control group were inconspicuous. A strong correlation between the Mankin score and TRAP‐positive cells could be found.ConclusionsAntigen‐induced arthritis causes severe damage in the TMJ of young rabbits. An improvement seems to be achievable by a systemic administration of etanercept.
How Do Interaction Activities among Customers and between Customers and Firms Influence Market Performance and Continuous Product Innovation? An Empirical Investigation of the Mobile Application Market
Authors: Jang Seongsoo , Chung Jaihak 
Published: June 2014

Mobile application markets (MAMs) significantly differ from other existing marketplaces at least in two aspects. First, customers (app users) and firms (app providers) frequently interact with each other in real time, which is not common in the conventional marketplaces. Second, many app providers incorporate customers’ opinions or suggestions into their software upgrades, representing one of the most unique and interesting aspects of MAMs. Therefore, it has become critical to understand the impact of interaction activities not only among customers, but also between customers and firms on the market performances of new products in MAMs. One of the most significant issues firms face is whether firms reflect on customers’ postpurchase interaction activities, and the next interesting question is how firms respond to them. This study explores the effects of customer‐to‐customer (C2C), customer‐to‐firm, and firm‐to‐customer interaction activities on market performance. In addition, this study investigates how communication activities influence a firm's tendency to pursue continuous product innovation through research and development (R&D).Using data obtained from a major MAM, T store, three models that are respectively related to product sales, product lifetime, and a firm's R&D activity for product upgrades, are applied to empirically test hypotheses concerning the effects of interaction activities. In our analyses of market performance, a hierarchical log regression model with 10,840 weekly transactions data set related to product sales (model A) and 291 aggregate transactions related to product lifetime (model B) is used. Results indicate that C2C and customer‐to‐firm communication activities have a positive impact on sales, but little relationship with product lifetime. However, a firm's continuous product R&D has a positive impact on both sales and lifetime performance. Our analysis of a firm's R&D (model C) shows that C2C and customer–firm communication increases a firm's R&D activity. Taken together, these results have important implications for customer–firm interactions, market performance, and R&D strategies.
Stress and Resilience for Parents of Children With Intellectual and Developmental Disabilities: A Review of Key Factors and Recommendations for Practitioners
Authors: Peer Justin W. , Hillman Stephen B. 
Published: June 2014

AbstractParents of children with intellectual and/or developmental disabilities experience more stress in comparison to parents of normally developing children. Chronic stress could negatively influence parents' health while also impacting their ability to meet their child's needs. Despite this, there is a subset of parents who remain resilient in the face of significant stress in their lives. Knowledge of the factors that promote parental resilience could positively impact the services these families receive. The authors conducted a systematic review of research article databases and found support for coping style, optimism, and social support as resilience factors for parents of children with intellectual and/or developmental disabilities. Awareness of variables that promote resilience for parents of children with intellectual and/or development disabilities is likely to inform clinical practice through offering new avenues for clinical focus in all phases of family‐centered care.