bluuebunny/crossref_metadata_2025 huggingface dataset:
It’s a Trap! Instructional Manipulation Checks Prompt Systematic Thinking on “Tricky” Tasks
Authors: Hauser David J. , Schwarz Norbert
Published: May 2015

Instructional manipulation checks (IMCs) have become popular tools for identifying inattentive participants in online studies. IMCs function by attempting to trick inattentive participants into responding incorrectly. However, from a conversational perspective, question characteristics are part of the researcher’s contribution to the conversation, and IMCs may teach participants that there is “more than meets the eye,” prompting systematic thinking on subsequent tricky-seeming questions in an attempt to avoid being tricked. In two online studies, participants responded to a simple task either before or after completing an IMC. As expected, answering an IMC prior to the task improved performance on items that benefit from increased systematic thinking—namely, the Cognitive Reflection Test (Study 1), and a probabilistic reasoning task (Study 2). We conclude that IMCs change attention rather than merely measure attention and discuss implications for their use in online studies.
Underreporting of Workplace Violence
Authors: Arnetz Judith E. , Hamblin Lydia , Ager Joel , Luborsky Mark , Upfal Mark J. , Russell Jim , Essenmacher Lynnette
Published: May 2015

This study examined differences between self-report and actual documentation of workplace violence (WPV) incidents in a cohort of health care workers. The study was conducted in an American hospital system with a central electronic database for reporting WPV events. In 2013, employees ( n = 2010) were surveyed by mail about their experience of WPV in the previous year. Survey responses were compared with actual events entered into the electronic system. Of questionnaire respondents who self-reported a violent event in the past year, 88% had not documented an incident in the electronic system. However, more than 45% had reported violence informally, for example, to their supervisors. The researchers found that if employees were injured or lost time from work, they were more likely to formally report a violent event. Understanding the magnitude of underreporting and characteristics of health care workers who are less likely to report may assist hospitals in determining where to focus violence education and prevention efforts.
Metabolic Syndrome Prevalence and Correlates in a Worksite Wellness Program
Authors: Johnson Paige , Turner Lori , Carter Melondie , Kelly Rebecca , Ewell Patrick J.
Published: May 2015

The purpose of this study was to examine the prevalence of metabolic syndrome among faculty and staff who participated in a university wellness program. In addition, this study identified common correlates of metabolic syndrome in the participating employee population. Knowledge of behaviors and characteristics of individuals with metabolic syndrome is essential when developing health promotion strategies for them. Metabolic syndrome is unique in that it results from a clustering of risk factors that are difficult to address, and each additional risk factor increasingly affects health and well-being. A targeted, comprehensive approach is needed to counteract individual’s predisposition to metabolic syndrome. This research identified the association between employees’ metabolic risks and their demographic, physical, and psychosocial characteristics in an effort to determine metabolic syndrome prevalence, develop population-specific interventions, and decrease the risk of metabolic syndrome among workers.
Infection Management and Health Practices Among Forensic Science Investigators in South Korea
Authors: Cha Kyeong-Sook , Cho Ok-Hee , Yoo Yang-Sook
Published: May 2015

This study investigated the current status of infection management for forensic science investigators in South Korea. This study included 104 forensic science investigators, of which 97.1% were exposed to the blood or body fluids of corpses during handling. Of these investigators, 98% claimed they wore gloves, and 12.9% used double-layered gloves. A total of 70.6% of the participants with relevant work experience wore masks to reduce infection risk; 43% wore gowns and goggles when at risk of contracting an infection. Furthermore, 59.8% of the investigators with pertinent work experience sought appropriate first aid and treatment when they experienced contaminated skin cuts or stab wounds. Working conditions and other problems should be analyzed consistently with the cooperation of employees, occupational health practitioners, and relevant organizations to prevent work-associated infections among forensic science investigators.
How I treat Waldenström macroglobulinemia
Authors: Treon Steven P.
Published: May 2015

Waldenström macroglobulinemia (WM) is a B-cell neoplasm manifested by the accumulation of clonal immunoglobulin (Ig)M-secreting lymphoplasmacytic cells. MYD88 and CXCR4 warts, hypogammaglobulinemia, infections, myelokathexis syndrome-like somatic mutations are present in >90% and 30% to 35% of WM patients, respectively, and impact disease presentation, treatment outcome, and overall survival. Familial predisposition is common in WM. Asymptomatic patients should be observed. Patients with disease-related hemoglobin <10 g/L, platelets <100 × 109/L, bulky adenopathy and/or organomegaly, symptomatic hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease, or transformed disease should be considered for therapy. Plasmapheresis should be used for patients with symptomatic hyperviscosity and before rituximab for those with high serum IgM levels to preempt a symptomatic IgM flare. Treatment choice should take into account specific goals of therapy, necessity for rapid disease control, risk of treatment-related neuropathy, immunosuppression and secondary malignancies, and planning for future autologous stem cell transplantation. Frontline treatments include rituximab alone or rituximab combined with alkylators (bendamustine and cyclophosphamide), proteasome inhibitors (bortezomib and carfilzomib), nucleoside analogs (fludarabine and cladribine), and ibrutinib. In the salvage setting, an alternative frontline regimen, ibrutinib, everolimus, or stem cell transplantation can be considered. Investigational therapies under development for WM include agents that target MYD88, CXCR4, BCL2, and CD27/CD70 signaling, novel proteasome inhibitors, and chimeric antigen receptor-modified T-cell therapy.
Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds
Authors: Lagrue Kathryn , Carisey Alex , Morgan David J. , Chopra Rajesh , Davis Daniel M.
Published: May 2015

Key Points

Lenalidomide augments nanoscale rearrangements in cortical actin at the human NK-cell immune synapse. Lenalidomide lowers the threshold for NK-cell activation, allowing activation by low levels of ligands on tumor cells.
CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL
Authors: Hagner Patrick R. , Man Hon-Wah , Fontanillo Celia , Wang Maria , Couto Suzana , Breider Mike , Bjorklund Chad , Havens Courtney G. , Lu Gang , Rychak Emily , Raymon Heather , Narla Rama Krishna , Barnes Leo , Khambatta Gody , Chiu Hsiling , Kosek Jolanta , Kang Jian , Amantangelo Michael D. , Waldman Michelle , Lopez-Girona Antonia , Cai Ti , Pourdehnad Michael , Trotter Matthew , Daniel Thomas O. , Schafer Peter H. , Klippel Anke , Thakurta Anjan , Chopra Rajesh , Gandhi Anita K.
Published: May 2015

Key Points

CC-122 is a novel agent for DLBCL with antitumor and immunomodulatory activity. CC-122 binds CRBN and degrades Aiolos and Ikaros resulting in a mimicry of IFN signaling and apoptosis in DLBCL.
Sequence-based ultra-dense genetic and physical maps reveal structural variations of allopolyploid cotton genomes
Authors: Wang Sen , Chen Jiedan , Zhang Wenpan , Hu Yan , Chang Lijing , Fang Lei , Wang Qiong , Lv Fenni , Wu Huaitong , Si Zhanfeng , Chen Shuqi , Cai Caiping , Zhu Xiefei , Zhou Baoliang , Guo Wangzhen , Zhang Tianzhen
Published: May 2015

Background

SNPs are the most abundant polymorphism type, and have been explored in many crop genomic studies, including rice and maize. SNP discovery in allotetraploid cotton genomes has lagged behind that of other crops due to their complexity and polyploidy. In this study, genome-wide SNPs are detected systematically using next-generation sequencing and efficient SNP genotyping methods, and used to construct a linkage map and characterize the structural variations in polyploid cotton genomes.

Results

We construct an ultra-dense inter-specific genetic map comprising 4,999,048 SNP loci distributed unevenly in 26 allotetraploid cotton linkage groups and covering 4,042 cM. The map is used to order tetraploid cotton genome scaffolds for accurate assembly of G. hirsutum acc. TM-1. Recombination rates and hotspots are identified across the cotton genome by comparing the assembled draft sequence and the genetic map. Using this map, genome rearrangements and centromeric regions are identified in tetraploid cotton by combining information from the publicly-available G. raimondii genome with fluorescent in situ hybridization analysis.

Conclusions

We report the genotype-by-sequencing method used to identify millions of SNPs between G. hirsutum and G. barbadense. We construct and use an ultra-dense SNP map to correct sequence mis-assemblies, merge scaffolds into pseudomolecules corresponding to chromosomes, detect genome rearrangements, and identify centromeric regions in allotetraploid cottons. We find that the centromeric retro-element sequence of tetraploid cotton derived from the D subgenome progenitor might have invaded the A subgenome centromeres after allotetrapolyploid formation. This study serves as a valuable genomic resource for genetic research and breeding of cotton.
Markers for the identification of tendon-derived stem cells in vitro and tendon stem cells in situ – update and future development
Authors: Lui Pauline Po Yee
Published: May 2015

The efficacy of tendon-derived stem cells (TDSCs) for the promotion of tendon and tendon-bone junction repair has been reported in animal studies. Modulation of the tendon stem cell niche in vivo has also been reported to influence tendon structure. There is a need to have specific and reliable markers that can define TDSCs in vitro and tendon stem cells in situ for several reasons: to understand the basic biology of TDSCs and their subpopulations in vitro; to understand the identity, niches and functions of tendon/progenitor stem cells in vivo; to meet the governmental regulatory requirements for quality of TDSCs when translating the exciting preclinical findings into clinical trial/practice; and to develop new treatment strategies for mobilizing endogenous stem/progenitor cells in tendon. TDSCs were reported to express the common mesenchymal stem cell (MSC) markers and some embryonic stem cell (ESC) markers, and there were attempts to use these markers to label tendon stem cells in situ. Are these stem cell markers useful for the identification of TDSCs in vitro and tracking of tendon stem cells in situ? This review aims to discuss the values of the panel of MSC, ESC and tendon-related markers for the identification of TDSCs in vitro. Important factors influencing marker expression by TDSCs are discussed. The usefulness and limitations of the panel of MSC, ESC and tendon-related markers for tracking stem cells in tendon, especially tendon stem cells, in situ are then reviewed. Future research directions are proposed.
Synthesis, characterization, and preclinical validation of a PET radiopharmaceutical for interrogating Aβ (β-amyloid) plaques in Alzheimer’s disease
Authors: Sundaram Guruswami SM , Dhavale Dhruva , Prior Julie L , Sivapackiam Jothilingam , Laforest Richard , Kotzbauer Paul , Sharma Vijay
Published: May 2015

Background

PET radiopharmaceuticals capable of imaging β-amyloid (Aβ) plaque burden in the brain could offer highly valuable diagnostic tools for clinical studies of Alzheimer’s disease. To further supplement existing armamentarium of FDA-approved agents as well as those under development, and to correlate multiphoton-imaging data reported earlier, herein, we describe preclinical validation of a PET tracer.

Methods

A novel PET radiopharmaceutical (18F-7B) was synthesized and characterized. To assess its affinity for Aβ, binding assays with Aβ1-42 fibrils, Alzheimer’s disease (AD) homogenates, and autoradiography studies and their IHC correlations were performed. For assessing its overall pharmacokinetic profiles in general and its ability to cross the blood-brain barrier (BBB) in particular, biodistribution studies in normal mice were performed. Finally, for evaluating potential for 18F-7B to serve as a targeted Aβ probe, the microPET/CT imaging was performed in age-matched amyloid precursor protein/presenilin-1 (APP/PS1) mice and wild-type (WT) counterparts.

Results

The radiotracer 18F-7B shows saturable binding to autopsy-confirmed AD homogenates (K
d = 17.7 nM) and Aβ1-42 fibrils (K
d = 61 nM). Preliminary autoradiography studies show binding of 18F-7B to cortical Aβ plaques in autopsy-confirmed AD tissue sections, inhibition of that binding by unlabeled counterpart 7A-indicating specificity, and a good correlation of tracer binding with Aβ immunostaining. The agent indicates high initial penetration into brains (7.23 ± 0.47%ID/g; 5 min) of normal mice, thus indicating a 5-min/120-min brain uptake clearance ratio of 4.7, a benchmark value (>4) consistent with the ability of agents to traverse the BBB to enable PET brain imaging. Additionally, 18F-7B demonstrates the presence of parental species in human serum. Preliminary microPET/CT imaging demonstrates significantly higher retention of 18F-7B in brains of transgenic mice compared with their WT counterparts, consistent with expected binding of the radiotracer to Aβ plaques, present in APP/PS1 mice, compared with their age-matched WT counterparts lacking those Aβ aggregates.

Conclusions

These data offer a platform scaffold conducive to further optimization for developing new PET tracers to study Aβ pathophysiology in vitro and in vivo.
Optimal site for facial nerve transection and neurorrhaphy: A randomized prospective animal study
Authors: Mendez Adrian I. , Seikaly Hadi , Biron Vincent , Zhu Lin-fu , Côté David W. J.
Published: May 2015

Background

Since the first facial allograft transplantation was performed, several institutions have performed the procedure with the main objectives being restoration of the aesthetic appearance and expressive function of the face. The optimal location to transect the facial nerve during flap harvest in transplantation to preserve facial movement function is currently unknown. There are currently two primary methods to perform facial nerve neurorrhaphy between the donor and recipient-one protocol involves transection and repair of the facial nerve at the main trunk while the another protocol advocates for the neurorrhaphy to be performed distally at the main branches. The purpose of this study is to establish the optimal location for transection and repair of the facial nerve to optimize functional recovery of facial movement.

Methods

A prospective randomized controlled trial using a rat model was performed. Two groups of 12 rats underwent facial nerve transection and subsequent repair either at the main trunk of the nerve (group 1) or 2 cm distally, at the main bifurcation (group 2). Primary outcome of nerve functional recovery was measured using a previously validated laser curtain model, which measured amplitude of whisking at 2, 4, and 6 post-operatively. The deflection of the laser curtain sent a digital signal that was interpreted by central computer software.

Results

At week 2 post-nerve surgery, the average amplitude observed for group 1 and 2 was 4.4 and 10.8 degrees, respectively. At week 4, group 1 showed improvement with an average amplitude of 9.7 degrees, while group 2 displayed an average of 10.2 degrees. The week 6 results showed the greatest improvement from baseline for group 1. Group 1 and 2 had average amplitudes of 17.2 and 6.9 degrees, respectively. There was no statistically significant difference between the two groups at 2, 4, and 6 weeks after facial nerve surgery ( p > 0.05).

Conclusions

We found no statistical difference between these two locations of nerve repair using identical methods. Therefore, the authors recommend a single versus multiple nerve repair technique. This finding has potential implications for future facial allograft transplantations and at minimum necessitates further study with long-term follow-up data.
Sexual dimorphism in echolocation pulse parameters of the CF-FM bat, Hipposideros pratti
Authors: Fu Zi-Ying , Dai Xing-Yue , Xu Na , Shi Qing , Li Gao-Jing , Li Bin , Li Juan , Li Jie , Tang Jia , Jen Philip Hung-Sun , Chen Qi-Cai
Published: May 2015

Background

Previous studies of sexual dimorphism in the echolocation pulses of the constant frequency-frequency modulating (CF-FM) bat have been mainly concentrated on the difference in the frequency of the CF component of the predominant second harmonic while neglected other pulse parameters. However, recent studies have shown that other pulse parameters of the predominant second harmonic are also biologically significant to the bat hunting. To complement and advance these studies, we have examined sexual dimorphism of multiple parameters (e.g., duration, frequency, bandwidth of the FM component, and repetition rate of emitted pulses) of the echolocation pulses of the CF-FM bat, Hipposideros pratti.

Results

Our studies of the predominant second harmonic show that on average the male bat has higher frequency of the CF component, wider FM bandwidth, and higher pulse repetition rate while the female bat has longer duration of the CF and FM components.

Conclusions

These observations suggest that bats may potentially use this sexual dimorphism in echolocation pulse parameters for social communication and species and sex identification.
Interactions between rat alveolar epithelial cells and bone marrow-derived mesenchymal stem cells: an in vitro co-culture model
Authors: Ito Hiroyuki , Uchida Tokujiro , Makita Koshi
Published: May 2015

Background

Bone marrow-derived mesenchymal stem cells (BMSCs) reduced the severity of acute lung injury after transplantation in multiple experimental studies, and several paracrine soluble factors secreted by the cells likely contribute to their therapeutic effect. The direct interactions between BMSCs and alveolar epithelial cells (AECs) may be an important part of their beneficial effects. Therefore, we assessed the interactions between BMSCs and AECs using a co-culture model of these two cell types from rats.

Methods

BMSCs and AECs were co-cultured using a Transwell system under the following conditions: (1) separated co-culture—AECs seeded on the insert and BMSCs in the base of the well; and (2) mixed co-culture—AECs on top of the monolayer of BMSCs on the culture insert and no cells in the base of the well. After 21 days of culture, the cells on the membrane of the culture insert were fixed and stained with antibodies against the receptor for advanced glycation end-products (RAGE), surfactant protein D (SP-D), and zona occludens protein-1, and then analyzed by confocal microscopy.

Results

In the separated co-culture condition, the phenotype of the AECs was maintained for 21 days, and cluster formation of SP-D-positive cells was induced in the AEC monolayer. We also found cluster formations of phospholipid-positive cells covered with RAGE-positive epithelial cells. In the mixed co-culture condition, the BMSCs induced alveolar-like structures covered with an epithelial cell layer. To determine the effect of keratinocyte growth factor (KGF) on this three-dimensional structure formation, we treated the mixed co-cultures with siRNA for KGF. While KGF siRNA treatment induced a significant reduction in surfactant protein transcript expression, formation of the alveolar-like structure was unaffected. We also assessed whether Gap26, a functional inhibitor of connexin-43, could mitigate the effect of the BMSCs on the AECs. However, even at 300 μM, Gap26 did not inhibit formation of the alveolar-like structure.

Conclusions

BMSCs release soluble factors that help maintain and sustain the AEC phenotype for 21 days, and direct interaction between these two cell types can induce a cyst-like, three-dimensional structure covered with AECs.
Matrix compliance and the regulation of cytokinesis
Authors: Sambandamoorthy Savitha , Mathew-Steiner Shomita , Varney Scott , Zuidema Jonathan M. , Gilbert Ryan J. , Van De Water Livingston , LaFlamme Susan E.
Published: May 2015

Integrin-mediated cell adhesion to the ECM regulates many physiological processes in part by controlling cell proliferation. It is well established that many normal cells require integrin-mediated adhesion to enter S phase of the cell cycle. Recent evidence indicates that integrins also regulate cytokinesis. Mechanical properties of the ECM can dictate entry into S phase; however, it is not known whether they also can affect the successful completion of cell division. To address this issue, we modulated substrate compliance using fibronectin-coated acrylamide-based hydrogels. Soft and hard substrates were generated with approximate elastic moduli of 1600 and 34,000 Pascals (Pa) respectively. Our results indicate that dermal fibroblasts successfully complete cytokinesis on hard substrates, whereas on soft substrates, a significant number fail and become binucleated. Cytokinesis failure occurs at a step following the formation of the intercellular bridge connecting presumptive daughter cells, suggesting a defect in abscission. Like dermal fibroblasts, mesenchymal stem cells require cell-matrix adhesion for successful cytokinesis. However, in contrast to dermal fibroblasts, they are able to complete cytokinesis on both hard and soft substrates. These results indicate that matrix stiffness regulates the successful completion of cytokinesis, and does so in a cell-type specific manner. To our knowledge, our study is the first to demonstrate that matrix stiffness can affect cytokinesis. Understanding the cell-type specific contribution of matrix compliance to the regulation of cytokinesis will provide new insights important for development, as well as tissue homeostasis and regeneration.
Dysregulated LIF-STAT3 pathway is responsible for impaired embryo implantation in a Streptozotocin-induced diabetic mouse model
Authors: Wang Tong-Song , Gao Fei , Qi Qian-Rong , Qin Fu-Niu , Zuo Ru-Juan , Li Zi-Long , Liu Ji-Long , Yang Zeng-Ming
Published: May 2015

The prevalence of diabetes is increasing worldwide with the trend of patients being young and creating a significant burden on health systems, including reproductive problems, but the effects of diabetes on embryo implantation are still poorly understood. Our study was to examine effects of diabetes on mouse embryo implantation, providing experimental basis for treating diabetes and its complications. Streptozotocin (STZ) was applied to induce type 1 diabetes from day 2 of pregnancy or pseudopregnancy in mice. Embryo transfer was used to analyze effects of uterine environment on embryo implantation. Our results revealed that the implantation rate is significantly reduced in diabetic mice compared to controls, and the change of uterine environment is the main reason leading to the decreased implantation rate. Compared to control, the levels of LIF and p-STAT3 are significantly decreased in diabetic mice on day 4 of pregnancy, and serum estrogen level is significantly higher. Estrogen stimulates LIF expression under physiological level, but the excessive estrogen inhibits LIF expression. LIF, progesterone or insulin supplement can rescue embryo implantation in diabetic mice. Our data indicated that the dysregulated LIF-STAT3 pathway caused by the high level of estrogen results in the impaired implantation in diabetic mice, which can be rescued by LIF, progesterone or insulin supplement.
Inexhaustible hair-cell regeneration in young and aged zebrafish
Authors: Pinto-Teixeira Filipe , Viader-Llargués Oriol , Torres-Mejía Elen , Turan Melissa , González-Gualda Estela , Pola-Morell Laura , López-Schier Hernán
Published: May 2015

Animals have evolved two general strategies to counter injury and maintain physiological function. The most prevalent is protection by isolating vital organs into body cavities. However, protection is not optimal for sensory systems because their external components need to be exposed to the environment to fulfill their receptive function. Thus, a common strategy to maintain sensory abilities against persistent environmental insult involves repair and regeneration. However, whether age or frequent injuries affect the regenerative capacity of sensory organs remains unknown. We have found that neuromasts of the zebrafish lateral line regenerate mechanosensory hair cells after recurrent severe injuries and in adulthood. Moreover, neuromasts can reverse transient imbalances of Notch signaling that result in defective organ proportions during repair. Our results reveal inextinguishable hair-cell regeneration in the lateral line, and suggest that the neuromast epithelium is formed by plastic territories that are maintained by continuous intercellular communication.
Structures, properties, and functions of the stings of honey bees and paper wasps: a comparative study
Authors: Zhao Zi-Long , Zhao Hong-Ping , Ma Guo-Jun , Wu Cheng-Wei , Yang Kai , Feng Xi-Qiao
Published: May 2015

Through natural selection, many animal organs with similar functions have evolved different macroscopic morphologies and microscopic structures. Here, we comparatively investigate the structures, properties and functions of honey bee stings and paper wasp stings. Their elegant structures were systematically observed. To examine their behaviors of penetrating into different materials, we performed penetration–extraction tests and slow motion analyses of their insertion process. In comparison, the barbed stings of honey bees are relatively difficult to be withdrawn from fibrous tissues (e.g. skin), while the removal of paper wasp stings is easier due to their different structures and insertion skills. The similarities and differences of the two kinds of stings are summarized on the basis of the experiments and observations.
Incubation temperature, morphology and performance in loggerhead (Caretta caretta) turtle hatchlings from Mon Repos, Queensland, Australia
Authors: Sim Elizabeth L. , Booth David T. , Limpus Colin J.
Published: May 2015

Marine turtles are vulnerable to climate change because their life history and reproduction are tied to environmental temperatures. The egg incubation stage is arguably the most vulnerable stage, because marine turtle eggs require a narrow range of temperatures for successful incubation. Additionally, incubation temperature affects sex, emergence success, morphology and locomotor performance of hatchlings. Hatchlings often experience high rates of predation in the first few hours of their life, and increased size or locomotor ability may improve their chances of survival. Between 2010 and 2013 we monitored the temperature of loggerhead (Caretta caretta; Linnaeus 1758) turtle nests at Mon Repos Rookery, and used these data to calculate a mean three day maximum temperature (T3dm) for each nest. We calculated the hatching and emergence success for each nest, then measured the mass, size and locomotor performance of hatchlings that emerged from those nests. Nests with a T3dm greater than 34°C experienced a lower emergence success and produced smaller hatchlings than nests with a T3dm lower than 34°C. Hatchlings from nests with a T3dm below 34°C performed better in crawling and swimming trials than hatchlings from nests with a T3dm above 34°C. Thus even non-lethal increases in global temperatures have the potential to detrimentally affect fitness and survival of marine turtle hatchlings.
How to make a midbrain dopaminergic neuron
Authors: Arenas Ernest , Denham Mark , Villaescusa J. Carlos
Published: May 2015

Midbrain dopaminergic (mDA) neuron development has been an intense area of research during recent years. This is due in part to a growing interest in regenerative medicine and the hope that treatment for diseases affecting mDA neurons, such as Parkinson's disease (PD), might be facilitated by a better understanding of how these neurons are specified, differentiated and maintained in vivo. This knowledge might help to instruct efforts to generate mDA neurons in vitro, which holds promise not only for cell replacement therapy, but also for disease modeling and drug discovery. In this Primer, we will focus on recent developments in understanding the molecular mechanisms that regulate the development of mDA neurons in vivo, and how they have been used to generate human mDA neurons in vitro from pluripotent stem cells or from somatic cells via direct reprogramming. Current challenges and future avenues in the development of a regenerative medicine for PD will be identified and discussed.
The matricellular protein CCN1 controls retinal angiogenesis by targeting VEGF, Src homology 2 domain phosphatase-1 and Notch signaling
Authors: Chintala Hemabindu , Krupska Izabela , Yan Lulu , Lau Lester , Grant Maria , Chaqour Brahim
Published: May 2015

Physiological angiogenesis depends on the highly coordinated actions of multiple angiogenic regulators. CCN1 is a secreted cysteine-rich and integrin-binding matricellular protein required for proper cardiovascular development. However, our understanding of the cellular origins and activities of this molecule is incomplete. Here, we show that CCN1 is predominantly expressed in angiogenic endothelial cells (ECs) at the leading front of actively growing vessels in the mouse retina. Endothelial deletion of CCN1 in mice using a Cre/Lox system is associated with EC hyperplasia, loss of pericyte coverage and formation of dense retinal vascular networks lacking the normal hierarchical arrangement of arterioles, capillaries and venules. CCN1 is a product of an immediate-early gene that is transcriptionally induced in ECs in response to stimulation by vascular endothelial growth factor (VEGF). We found that CCN1 activity is integrated with VEGF receptor 2 (VEGF-R2) activation and downstream signaling pathways required for tubular network formation. CCN1-integrin binding increased the expression of and association between Src homology 2 domain–containing protein tyrosine phosphatase-1 (SHP-1) and VEGF-R2 which leads to rapid dephosphorylation of VEGF-R2 tyrosine preventing EC hyperproliferation. Predictably, CCN1 further brings receptors/signaling molecules into proximity that are otherwise spatially separated. Furthermore, CCN1 induces integrin-dependent Notch activation in cultured ECs and its targeted gene inactivation in vivo alters Notch-dependent vascular specification and remodeling suggesting that functional levels of Notch signaling requires CCN1 activity. These data highlight novel functions of CCN1 as a naturally optimized molecule fine controlling key processes in physiological angiogenesis and safeguarding against aberrant angiogenic responses.
The myelin proteolipid plasmolipin forms oligomers and induces liquid-ordered membranes in the Golgi complex
Authors: Yaffe Yakey , Hugger Ilan , Yassaf Inbar Nevo , Shepshelovitch Jeanne , Sklan Ella H. , Elkabetz Yechiel , Yeheskel Adva , Pasmanik-Chor Metsada , Benzing Carola , Macmillan Alexander , Gaus Katharina , Eshed-Eisenbach Yael , Peles Elior , Hirschberg Koret
Published: May 2015

Myelin comprises a compactly stacked massive surface area of protein-poor thick membrane that insulates axons to allow fast signal propagation. Increasing levels of the myelin protein plasmolipin (PLLP) were correlated with post-natal myelination; however, its function is unknown. Here, the intracellular localization and dynamics of PLLP were characterized in primary glial and cultured cells using fluorescently labeled PLLP and antibodies against PLLP. PLLP localized to and recycled between the plasma membrane and the Golgi complex. In the Golgi complex, PLLP forms oligomers based on fluorescence resonance energy transfer (FRET) analyses. PLLP oligomers blocked Golgi to plasma membrane transport of the secretory protein vesicular stomatitis virus G protein (VSVG), but not of a VSVG mutant with an elongated transmembrane domain. Laurdan staining analysis showed that this block is associated with PLLP-induced proliferation of liquid-ordered membranes. These findings show the capacity of PLLP to assemble potential myelin membrane precursor domains at the Golgi complex through its oligomerization and ability to attract liquid-ordered lipids. These data support a model in which PLLP functions in myelin biogenesis through organization of myelin liquid-ordered membranes in the Golgi complex.
ESCRTs regulate amyloid precursor protein sorting in multivesicular bodies and intracellular beta amyloid accumulation
Authors: Edgar James R. , Willén Katarina , Gouras Gunnar K. , Futter Clare E.
Published: May 2015

Intracellular beta amyloid (Aβ) accumulation is a key feature of early Alzheimer's disease (AD) and precedes the appearance of Aβ in extracellular plaques. Aβ is generated through proteolytic processing of amyloid precursor protein (APP), but the intracellular site of Aβ production is unclear. APP has been localized to multivesicular endosomes/bodies (MVBs) where sorting of APP onto ILVs could promote amyloidogenic processing or reduce Aβ production/accumulation by sorting APP and processing products to lysosomes for degradation. We show that APP localizes to the ILVs of a subset of MVBs that also traffic EGF receptor (EGFR), and is delivered to lysosomes for degradation. Depletion of the ESCRT components, Hrs or Tsg101, inhibited targeting of APP to ILVs and the subsequent delivery to lysosomes and lead to increased intracellular Aβ accumulation. This was accompanied by dramatically decreased Aβ secretion. Thus, the early ESCRT machinery has a dual role in limiting intracellular Aβ accumulation through targeting of APP and processing products to the lysosome for degradation and promoting Aβ secretion.
LARP4B is an AU-rich sequence associated factor that promotes mRNA accumulation and translation
Authors: Küspert Maritta , Murakawa Yasuhiro , Schäffler Katrin , Vanselow Jens T. , Wolf Elmar , Juranek Stefan , Schlosser Andreas , Landthaler Markus , Fischer Utz
Published: May 2015

mRNAs are key molecules in gene expression and subject to diverse regulatory events. Regulation is accomplished by distinct sets of trans-acting factors that interact with mRNAs and form defined mRNA–protein complexes (mRNPs). The resulting “mRNP code” determines the fate of any given mRNA and thus controlling gene expression at the post-transcriptional level. The La-related protein 4B (LARP4B) belongs to an evolutionarily conserved family of RNA-binding proteins characterized by the presence of a La-module implicated in direct RNA binding. Biochemical experiments have shown previously direct interactions of LARP4B with factors of the translation machinery. This finding along with the observation of an association with actively translating ribosomes suggested that LARP4B is a factor contributing to the mRNP code. To gain insight into the function of LARP4B in vivo we tested its mRNA association at the transcriptome level and its impact on the proteome. PAR-CLIP analyses allowed us to identify the in vivo RNA targets of LARP4B. We show that LARP4B binds to a distinct set of cellular mRNAs by contacting their 3′ UTRs. Biocomputational analysis combined with in vitro binding assays identified the LARP4B-binding motif on mRNA targets. The reduction of cellular LARP4B levels leads to a marked destabilization of its mRNA targets and consequently their reduced translation. Our data identify LARP4B as a component of the mRNP code that influences the expression of its mRNA targets by affecting their stability.
DcpS is a transcript-specific modulator of RNA in mammalian cells
Authors: Zhou Mi , Bail Sophie , Plasterer Heather L. , Rusche James , Kiledjian Megerditch
Published: May 2015

The scavenger decapping enzyme DcpS is a multifunctional protein initially identified by its property to hydrolyze the resulting cap structure following 3′ end mRNA decay. In Saccharomyces cerevisiae, the DcpS homolog Dcs1 is an obligate cofactor for the 5′-3′ exoribonuclease Xrn1 while the Caenorhabditis elegans homolog Dcs-1, facilitates Xrn1 mediated microRNA turnover. In both cases, this function is independent of the decapping activity. Whether DcpS and its decapping activity can affect mRNA steady state or stability in mammalian cells remains unknown. We sought to determine DcpS target genes in mammalian cells using a cell-permeable DcpS inhibitor compound, RG3039 initially developed for therapeutic treatment of spinal muscular atrophy. Global mRNA levels were examined following DcpS decapping inhibition with RG3039. The steady-state levels of 222 RNAs were altered upon RG3039 treatment. Of a subset selected for validation, two transcripts that appear to be long noncoding RNAs HS370762 and BC011766, were dependent on DcpS and its scavenger decapping catalytic activity and referred to as DcpS-responsive noncoding transcripts (DRNT) 1 and 2, respectively. Interestingly, only the increase in DRNT1 transcript was accompanied with an increase of its RNA stability and this increase was dependent on both DcpS and Xrn1. Importantly, unlike in yeast where the DcpS homolog is an obligate cofactor for Xrn1, stability of additional Xrn1 dependent RNAs were not altered by a reduction in DcpS levels. Collectively, our data demonstrate that DcpS in conjunction with Xrn1 has the potential to regulate RNA stability in a transcript-selective manner in mammalian cells.
Effect of Vibration Properties of a Resonance Board on Piano Timbre
Authors: Miao Yuanyuan , Liu Zhenbo , Liu Yixing , Shen Jun
Published: May 2015

The resonance board is one of the most important components of a piano and greatly affects the piano's timbre. The vibration properties of eight resonance boards made from Picea glehnii, Picea jezoensis, Picea spinulosa, and Picea sitchensis were analyzed using the spectrum analysis method of the fast Fourier transform following vibration theory. The modulus of elasticity (E) and velocity of vibration transmission (C) of each resonance board were calculated. After the resonance boards were incorporated into pianos, the mean amplitude, ratio of maximum to minimum amplitudes, and mean ratio of successive amplitudes of resonant frequencies for 36 typical keys of each piano were obtained from the frequency spectrum. The correlation between a piano's timbre and the resonance board's vibration properties was analyzed. The results show that the piano timbre improves with increasing E and C, especially in the y direction of the resonance board.
Whose side are we on and for whom do we write? Notes on issues and challenges facing those researching and evaluating public policy
Authors: Warren Jon , Garthwaite Kayleigh
Published: May 2015

Becker (1967) poses the question Whose side are we on?, a question which has become an enduring part of discussions within social scientific methodology. This paper explores the key issues in Becker’s argument and considers its relevance to researchers today, locating this within a consideration of evaluation-based research and policy. Many of the issues Becker discusses remain relevant, yet what has changed radically is the context within which academics operate. In an era when academics and their research are becoming increasingly commodified, this paper contends that the question of who the academic serves and writes for is increasingly important.
Silencing SOX2 Expression by RNA Interference Inhibits Proliferation, Invasion and Metastasis, and Induces Apoptosis through MAP4K4/JNK Signaling Pathway in Human Laryngeal Cancer TU212 Cells
Authors: Yang Ning , Wang Yan , Hui Lian , Li Xiaotian , Jiang Xuejun
Published: May 2015

SRY (sex determining region Y)-box 2 (SOX2) plays an important role in tumor cell metastasis and apoptosis. Laryngeal squamous cell carcinoma (LSCC), responsible for 1.5% of all cancers, is one of the most common head and neck malignancies. Accumulating evidence shows that SOX2 is overexpressed in several human tumors, including lung cancer, esophageal carcinoma, pancreatic carcinoma, breast cancer, ovarian carcinoma and glioma. Our study aimed to investigate the silencing effects of SOX2 expression using RNA interference (RNAi) on various biological processes in laryngeal cancer TU212 cells, including proliferation, apoptosis, invasion and metastasis. We also studied the involvement of the MAPK/JNK signaling pathway in the biological effects of SOX2 siRNA in TU212 cells. We found that silencing SOX2 decreased the proliferation, migration, and invasion of TU212 cells, and induced apoptosis. This effect of silencing SOX2 could be reversed by silencing MAP4K4. Therefore, we consider SOX2 as a key regulator of the upstream MAP4K4/JNK signaling pathways that could be a potential therapeutic target in the treatment of patients with or prevention of laryngeal cancer.
Decorin in Human Colon Cancer
Authors: Nyman Marie C. , Sainio Annele O. , Pennanen Mirka M. , Lund Riikka J. , Vuorikoski Sanna , Sundström Jari T. T. , Järveläinen Hannu T.
Published: May 2015

Decorin is generally recognized as a tumor suppressing molecule. Nevertheless, although decorin has been shown to be differentially expressed in malignant tissues, it has often remained unclear whether, in addition to non-malignant stromal cells, cancer cells also express it. Here, we first used two publicly available databases to analyze the current information about decorin expression and immunoreactivity in normal and malignant human colorectal tissue samples. The analyses demonstrated that decorin expression and immunoreactivity may vary in cancer cells of human colorectal tissues. Therefore, we next examined decorin expression in normal, premalignant and malignant human colorectal tissues in more detail using both in situ hybridization and immunohistochemistry for decorin. Our results invariably demonstrate that malignant cells within human colorectal cancer tissues are devoid of both decorin mRNA and immunoreactivity. Identical results were obtained for cells of neuroendocrine tumors of human colon. Using RT-qPCR, we showed that human colon cancer cell lines are also decorin negative, in accordance with the above in vivo results. Finally, we demonstrate that decorin transduction of human colon cancer cell lines causes a significant reduction in their colony forming capability. Thus, strategies to develop decorin-based adjuvant therapies for human colorectal malignancies are highly rational.
Four Months, Three Weeks and Two Days (2007) and Beyond the Hills (2012): Romanian auteur Cristian Mungiu and the paradoxes of ‘anti-national national cinema’
Authors: Goss Brian Michael
Published: May 2015

This discussion of Romanian director Cristian Mungiu’s internationally circulated ‘popular highbrow’ films – 4 luni, 3 saptamâni si 2 zile/Four Months, Three Weeks and Two Days (2007); and Dupa dealuri/Beyond the Hills (2012) – is grounded in the auteur theory. In particular, the analysis telescopes in on the thematic motif of surveillance that animates the two films. At the same time, on a Foucauldian view, the motif plays out in distinct forms in each cinematic text. In Four Months, Three Weeks and Two Days, surveillance in the late Ceaus¸escu-era is depicted as gaining expression through the internalized discipline of the monadic subject. In contrast, in the contemporaneous Beyond the Hills, surveillance implicates the practices of the pure community convened in distinction to an exiled other. Psychoanalytic concepts (primal crime, return of the repressed) are also summoned to tease out the social tensions in the films. Mungiu’s work vigorously cross-­examines the official mythologies of national harmony; in other words, Mungiu may be construed as engaging with what Mike Wayne calls ‘anti-national national cinema’. However laudable the practice of socially conscious critical film is, auto-problematization of ‘peripheral’ nations may also bring reproduction of marginalization in its train when the films circulate internationally.
Canonic formations and non-canonic positionings: The case of post-millennium Danish popular music
Authors: Marstal Henrik
Published: May 2015

This article investigates ways in which canonic discourses form part of the everyday popular music culture among both audiences and music critics in the early twenty-first century. By analysing reviews in which artists and albums of the so-called New Danish Wave are juxtaposed with Danish canonic artists and albums from the 1960s to the 1980s, it is argued that canonic discourse forms an important, yet unreflected or even unnoticed vehicle for the reception of the music in question. Even though a canonical fragmentation during the turn of the millennium may be identified on a global scale, the incident shows how national agendas and positions are able to go against this trend in a small-scale nation like Denmark.
Reviews
Authors: Coventry Rachel , Goss Brian Michael , Babbington Bruce
Published: May 2015

Roald Dahl and Philosophy: A Little Nonsense Now and Then, Jacob M. Held (ed.) (2014) 1st ed., Plymouth: Rowman & Littlefield, 243 pp., ISBN: 9781442222526, p/bk, £11.95

Contemporary Romanian Cinema: The History of an Unexpected Miracle, Dominique Nasta (2013) 1st ed., London: Wallflower Press, 256 pp. ISBN: 9780231167451, p/bk, £18.00; ISBN: 9780231167444, h/bk, £55.00

From Communism to Capitalism: Nation and State in Romanian Cultural Production, Florentina C. Andreescu (2013) 1st ed., New York: Palgrave Macmillan, 200 pp., ISBN: 9781137276919, h/bk, £62.50

Sport and Film, Seán Crosson (2013) Abingdon, Oxon: Routledge, ISBN: 9780415569927, h/bk; ISBN: 9780415569934, p/bk, £78.40/£22.87
The Spectrum of Neuroendocrine Tumors: Histologic Classification, Unique Features and Areas of Overlap
Authors: Klimstra David S. , Beltran Himisha , Lilenbaum Rogerio , Bergsland Emily
Published: May 2015

Neuroendocrine neoplasms are diverse in terms of sites of origin, functional status, and degrees of aggressiveness. This review will introduce some of the common features of neuroendocrine neoplasms and will explore the differences in pathology, classification, biology, and clinical management between tumors of different anatomic sites, specifically, the lung, pancreas, and prostate. Despite sharing neuroendocrine differentiation and histologic evidence of the neuroendocrine phenotype in most organs, well-differentiated neuroendocrine tumors (WD-NETs) and poorly differentiated neuroendocrine carcinomas (PD-NECs) are two very different families of neoplasms. WD-NETs (grade 1 and 2) are relatively indolent (with a natural history that can evolve over many years or decades), closely resemble non-neoplastic neuroendocrine cells, and demonstrate production of neurosecretory proteins, such as chromogranin A. They arise in the lungs and throughout the gastrointestinal tract and pancreas, but WD-NETs of the prostate gland are uncommon. Surgical resection is the mainstay of therapy, but treatment of unresectable disease depends on the site of origin. In contrast, PD-NECs (grade 3, small cell or large cell) of all sites often demonstrate alterations in P53 and Rb, exhibit an aggressive clinical course, and are treated with platinum-based chemotherapy. Only WD-NETs arise in patients with inherited neuroendocrine neoplasia syndromes (e.g., multiple endocrine neoplasia type 1), and some common genetic alterations are site-specific (e.g., TMPRSS2-ERG gene rearrangement in PD-NECs arising in the prostate gland). Advances in our understanding of the molecular basis of NETs should lead to new diagnostic and therapeutic strategies and is an area of active investigation.