bluuebunny/crossref_metadata_2025_split huggingface dataset:
A second generation IL-2 receptor-targeted diphtheria fusion toxin exhibits anti-tumor activity and synergy with anti-PD-1 in melanoma
Authors: Cheung Laurene S. , Fu Juan , Kumar Pankaj , Kumar Amit , Urbanowski Michael E. , Ihms Elizabeth A. , Parveen Sadiya , Bullen C. Korin , Patrick Garrett , Harrison Robert , Murphy John R. , Pardoll Drew M. , Bishai William R. 
Published: September 2018

AbstractDenileukin diftitox (DAB1-389-IL-2, Ontak®) is a diphtheria toxin-based fusion protein that depletes CD25-positive cells including regulatory T cells (Tregs) and was approved for the treatment of persistent or recurrent cutaneous T cell lymphoma. However, the clinical use of denileukin diftitox was limited by vascular leak toxicity and production issues related to drug aggregation and purity. We found that a single amino acid substitution (V6A) in a motif associated with vascular leak induction yields a fully active, second-generation biologic, s-DAB1-386-IL-2(V6A), which elicits 50-fold less HUVEC monolayer permeation and is 3.7-fold less lethal to mice by LD50analysis than s-DAB1-386-IL-2 Additionally, to overcome aggregation problems, we developed a novel production method for the fusion toxin usingCorynebacterium diphtheriaethat secretes fully-folded, biologically active, monomeric s-DAB1-386-IL-2 into the culture medium. Using the poorly immunogenic mouse B16F10 melanoma model, we initiated treatment 7 days after tumor challenge and observed that, while both s-DAB1-386-IL-2(V6A) and s-DAB1-386-IL-2 are inhibitors of tumor growth, the capacity to treat with higher doses of s-DAB1-386-IL-2(V6A) could provide a superior activity window. In a sequential dual therapy study in tumors that have progressed for 10 days both s-DAB1-386-IL-2(V6A) and s-DAB1-386-IL-2 given prior to checkpoint inhibition with anti-PD-1 antibodies inhibited tumor growth, while either drug given as monotherapy had less effect. s-DAB1-386-IL-2(V6A), a fully monomeric protein with reduced vascular leak, is a second-generation diphtheria toxin-based fusion protein with promise as a cancer immunotherapeutic both alone and in conjunction with PD-1 blockade.Significance StatementRegulatory T cells (Tregs) infiltrate tumors in various cancers and promote an immunosuppressive microenvironment that hinders anti-tumor immunity. Denileukin diftitox, a diphtheria toxin-based fusion protein that depletes Tregs, was approved for the treatment of T cell malignancies, but its clinical use was limited due to the presence of protein aggregates and toxicity associated with vascular leakage. Here we report the production of a second generation IL-2 receptor-targeted, fully-folded, monomeric diphtheria fusion toxin, and a V6A mutant variant which showed reduced vascular leak in vitro and reduced lethality in mice. In a mouse model of melanoma, we found significant decrease in tumor growth associated with reduction in Tregs when the protein was tested as monotherapy or in combination with checkpoint blockade.
A TauP301L mouse model of dementia; development of pathology, synaptic transmission, microglial response and cognition throughout life
Authors: Joel Zelah , Izquierdo Pablo , Liu Wenfei , Hall Chloe , Roberts Martha , Yap Kenrick , Nick Amy , Spowart Emma , Desai Roshni , Muessig Laurenz , Steinberg Rivka , Martin Stuart , Smith Kenneth J , Richardson Jill C , Cacucci Francesca , Salih Dervis A. , Cummings Damian M. , Edwards Frances A. 
Published: September 2018

AbstractBackgroundLate stage Alzheimer’s disease and other dementias are associated with neurofibrillary tangles and neurodegeneration. Here we describe a mouse (TauD35) carrying human Tau with the P301L mutation that results in Tau hyperphosphorylation and tangles. Previously we have compared gene expression in TauD35 mice to mice which develop plaques but no tangles. A similar comparison of other pathological features throughout disease progression is made here between amyloidβ and Tau mice described in Parts I and II of this study.MethodsIn vitro CA1 patch clamp and field recordings were used to investigate synaptic transmission and plasticity. Plaque load and microglia were investigated with immunohistochemistry. Cognition, locomotor activity and anxiety-related behaviours were assessed with a forced-alternation T-maze, open field and light/dark box.ResultsTransgene copy number in TauD35 mice fell into two groups (HighTAU and LowTAU), allowing assessment of dose-dependent effects of overexpression and resulting in tangle load increasing 100-fold for a 2-fold change in protein levels. Tangles were first detected at 8 (HighTAU) or 13 months (LowTAU) but the effects on synaptic transmission and plasticity and behaviour were subtle. However, severe neurodegeneration occurred in HighTAU mice at around 17 months, preceded by considerable proliferation and activation of microglia at 13 months of age; both increasing further at 17 months. LowTAU mice at 24 months of age showed a comparable tangle load and microglial proliferation to that occurring at 13 months in HighTAU mice. However, LowTAU mice showed no neurodegeneration at this stage and considerable microglial activation, stressing the dependence of these effects on overexpression and/or age.ConclusionsComparison of the effects of amyloidβ and plaques without tangles in a model of preclinical Alzheimer’s disease to the effects of tangles without amyloidβ plaques in the late stage model described here may clarify the progressive stages of Alzheimer’s disease. While Tau hyperphosphorylation and neurofibrillary tangles are eventually sufficient to cause severe neurodegeneration, initial effects on synaptic transmission and the immune response are subtle. In contrast while even with a heavy plaque load little if any neurodegeneration occurs, considerable effects on synaptic transmission and the immune system result, even before plaques are detectable.
Pitch perception is adapted to species-specific cochlear filtering
Authors: Walker Kerry MM , Gonzalez Ray , Kang Joe , McDermott Josh H , King Andrew J 
Published: September 2018

AbstractPitch perception is critical for recognizing speech, music and animal vocalizations, but its neurobiological basis remains unsettled, in part because of divergent results from different species. We used a combination of behavioural measurements and cochlear modelling to investigate whether species-specific differences exist in the cues used to perceive pitch and whether these can be accounted for by differences in the auditory periphery. Ferrets performed a pitch discrimination task well whenever temporal envelope cues were robust, but not when resolved harmonics only were available. By contrast, human listeners exhibited the opposite pattern of results on an analogous task, consistent with previous studies. Simulated cochlear responses in the two species suggest that the relative salience of the two types of pitch cues can be attributed to differences in cochlear filter bandwidths. Cross-species variation in pitch perception may therefore reflect the constraints of estimating a sound’s fundamental frequency given species-specific cochlear tuning.
Loss of zebrafish ctnnd2b results in disorganised forebrain neuron clusters
Authors: Hofmeister Wolfgang , Vaz Raquel , Edwards Steven , Dueñas Rey Alfredo , Lindstrand Anna 
Published: September 2018

AbstractDelta catenin (CTNND2) is an adhesive junction associated protein belonging to the family of p120ct catenins. It is located on the short arm of chromosome 5, a region deleted in Cri-du-chat syndrome. Heterozygous loss of CTNND2 function has been linked to autism, schizophrenia, and mild intellectual disability with or without dyslexia-like learning difficulties. To date, most functional studies have focused on homozygous loss of the gene, contradictory to the dominant effect of loss of a single allele observed in neurodevelopmental disorders. Here we show that heterozygous loss of ctnnd2b results in a disorganisation and imbalance of neuronal subtypes in forebrain specific regions. Using the zebrafish model, we show that CRISPR/Cas9-induced loss of ctnnd2b but not ctnnd2a results in an increase in isl1-expressing cells and a local reduction of GABA expressing neurons in the optic recess region of the embryonic zebrafish forebrain. Using time-lapse analysis, we found that the disorganised distribution of is1l-expressing forebrain neurons was not due to migration defects, but rather an increase in the number of isl1-GFP neurons in the optic recess region. Upon closer analysis, these neurons appear disorganised and show an altered morphology and orientation. Overall this data suggests that ctnnd2 may affect the differentiation cascade of neuronal subtypes in specific regions of the vertebrate brain.
A Streamlined Process to Phenotypically Profile Heterologous cDNAs in Parallel Using Yeast Cell-Based Assays
Authors: Tugendreich Stuart , Perkins Ed , Couto Joe , Barthmaier Peter , Sun Dongxu , Tang Shawn , Tulac Suzana , Nguyen Allen , Yeh Elaine , Mays Amy , Wallace Ellen , Lila Tom , Shivak Dave , Prichard Mark , Andrejka Laura , Kim Raymond , Melese Teri 
Published: September 2018

To meet the demands of developing lead drugs for the profusion of human genes being sequenced as part of the human genome project, we developed a high-throughput assay construction method in yeast. A set of optimized techniques allows us to rapidly transfer large numbers of heterologous cDNAs from nonyeast plasmids into yeast expression vectors. These high- or low-copy yeast expression plasmids are then converted quickly into integration-competent vectors for phenotypic profiling of the heterologous gene products. The process was validated first by testing proteins of diverse function, such as p38, poly(ADP-ribose) polymerase-1, and PI 3-kinase, by making active-site mutations and using existing small molecule inhibitors of these proteins. For less well-characterized genes, a novel random mutagenesis scheme was developed that allows a combination selection/screen for mutations that retain full-length expression and yet reverse a growth phenotype in yeast. A broad range of proteins in different functional classes has been profiled, with an average yield for growth interference phenotypes of ∼30%. The ease of manipulation of the yeast genome affords us the opportunity to approach drug discovery and exploratory biology on a genomic scale and shortens assay development time significantly.[The sequence data described in this paper have been submitted to the data library under accession no. AF359244.]
Mathematical models and simulated annealing algorithms for the robotic assembly line balancing problem
Authors: Li Zixiang , Janardhanan Mukund Nilakantan , Nielsen Peter , Tang Qiuhua 
Published: September 2018

Purpose
Robots are used in assembly lines because of their higher flexibility and lower costs. The purpose of this paper is to develop mathematical models and simulated annealing algorithms to solve the robotic assembly line balancing (RALB-II) to minimize the cycle time.

Design/methodology/approach
Four mixed-integer linear programming models are developed and encoded in CPLEX solver to find optimal solutions for small-sized problem instances. Two simulated annealing algorithms, original simulated annealing algorithm and restarted simulated annealing (RSA) algorithm, are proposed to tackle large-sized problems. The restart mechanism in the RSA methodology replaces the incumbent temperature with a new temperature. In addition, the proposed methods use iterative mechanisms for updating cycle time and a new objective to select the solution with fewer critical workstations.

Findings
The comparative study among the tested algorithms and other methods adapted verifies the effectiveness of the proposed methods. The results obtained by these algorithms on the benchmark instances show that 23 new upper bounds out of 32 tested cases are achieved. The RSA algorithm ranks first among the algorithms in the number of updated upper bounds.

Originality/value
Four models are developed for RALBP-II and their performance is evaluated for the first time. An RSA algorithm is developed to solve RALBP-II, where the restart mechanism is developed to replace the incumbent temperature with a new temperature. The proposed methods also use iterative mechanisms and a new objective to select the solution with fewer critical workstations.
Online digital library sampling based on query related graph
Authors: Liu Wei , Su Jing 
Published: September 2018

Purpose
Digital library sampling is used to obtain a collection of random literature records from the backend database, which is a crucial issue for a variety of important purposes in many online digital library applications. Digital libraries can only be accessed through their query interfaces. The challenge is how to ensure the randomness of the sample via the autonomous query interface.

Design/methodology/approach
This paper presents an iterative and incremental approach to obtain samples through the query interface of a digital library. In the approach, a novel graph model, query-related graph, is proposed to transform the flat literature records into a graph structure, and samples are obtained iteratively by traveling the query-related graph. Besides query-related graph, the key components, query generation, termination condition and amending deviation, are also discussed in detail.

Findings
The extensive experiments over two real digital libraries, ISTIC and IEEE Xplore, show the proposed approach results in a better performance. First, the approach is very effective to obtain high-quality samples which are evaluated by the measure “sample deviation.” Second, the sampling process is very efficient by only submitting fewer random queries. Third, the approach is robust.

Research limitations/implications
This sampling approach is limited by the query interfaces on a web page. In rare cases (<3 per cent), this approach cannot access query interfaces by sophisticated techniques.

Practical implications
Digital library sampling is very useful for a variety of important purposes: subject distribution analysis, literature quality evaluation, digital library size estimation, source selection in digital library integration and content freshness evaluation.

Social implications
Myriads of online digital libraries can be accessed online. Digital library sampling is a useful way to understand digital libraries for many important applications.

Originality/value
Most of the attributes of a digital library query interface have infinite values, such as keyword attributes, which cannot be handled effectively by the existing sampling approaches.
Accentuating the positive
Authors: Edgar Fiona , Geare Alan , Zhang Jing A. 
Published: September 2018

PurposeThe positive psychology movement suggests organisational behaviourists should accentuate the positive by increasing the attention paid to the enhancement of employee wellness. This fits comfortably with the ethos of human resource management which is rooted in notions of social exchange, reciprocity and mutual gain. The purpose of this paper is to inject some positivity into HRM research by examining the mediating role of positive emotions in the HRM–performance relationship.Design/methodology/approachTo examine the role played by positive emotions in the relationship between HRM and citizenship behaviours, the authors surveyed a sample of 250 employees from 14 organisations in New Zealand service industries. Sobel and bootstrapping tests were used to examine the mediation model.FindingsResults show positive emotional states, both personal and job-related, to positively and partially mediate the HRM–contextual performance relationship.Research limitations/implicationsTheoretically, this finding opens up HRM’s black box affording support for the inclusion of a wider range of psychological states than those presently studied.Practical implicationsSupport is provided for HRM approaches which are more progressive than remedial in nature.Originality/valueEmotions are malleable and this study suggests that fostering positive emotional states might hold the key to performance, unlocking desirable employee behaviours.
Are corporate office buildings priced differently?
Authors: Costa Odilon , Fuerst Franz , Mendes-da-Silva Wesley 
Published: September 2018

PurposeWhile broader property-type categories of real estate markets have been scrutinized at microeconomic level in some segments – namely, residential, retail, industrial and hospitality, there is limited evidence showing that local office markets can be viewed as monolithic and economically integrated entities. The purpose of this paper is to investigate how occupiers differ in their willingness to pay for principal office rent determinants in the corporate and non-corporate sectors.Design/methodology/approachA sample of properties located in the largest office market in Latin America is partitioned based on the average size of leasable units. This approach captures interactions between different groups of investors and occupiers, and is commonly adopted by local market practitioners due to lack of detailed information on market participants. The pricing schedules for these two groups of buildings are then empirically compared through hedonic regression analysis and parameter stability tests.FindingsThe regressions show that corporate and smaller occupier properties form distinct spatial and non-spatial submarkets, but that their temporal patterns are quite similar. Thus, these property-type segments can be classified as imperfect substitutes with distinct pricing schemes, but not as a unique market, as their pricing schedules are not generalizable.Practical implicationsThe results imply that “office properties” are too complex and disparate to be reliably examined with a simple aggregate approach as practiced in developed office market research since the 1980s. The fragmented reality of office properties has important implications for investment decisions and real estate valuation.Originality/valueThis paper shows that the corporate office market exhibits distinct characteristics and key determinants of office price and rent valuation differ significantly between the corporate and non-corporate segments. The corollary of these findings is that market studies that require reliable estimates of price drivers may be enriched by modeling these two segmented markets separately. It is also important to note that this distinction cuts across the established A/B/C office space quality classification.
Individualized Cool Dialysate as an Effective Therapy for Intradialytic Hypotension and Hemodialysis Patients’ Perception
Authors: Bullen Alexander , Rifkin Dena , Trzebinska Danuta 
Published: September 2018

AbstractIntradialytic hypotension (IDH) is the most common dialytic complication. Recurrent episodes of ischemia secondary to hemodynamic instability are associated with cardiomyopathy, increased risk of thrombosis of arteriovenous fistula, decreased quality of life, and increased mortality. Cool dialysate may be an effective approach to reducing intradialytic hypotension by promoting peripheral vasoconstriction. Most studies to date are small and do not employ individualized cool dialysates (ICD). The study consisted of standard and cool phases, with patients as their own controls. During the standard phase, participants underwent hemodialysis (HD) at their usual dialysate temperature at 37°C for six consecutive hemodialysis sessions. In the cool phase, the dialysate temperature was set at the core baseline temperature −0.5°C for six more sessions. We compared hemodynamic parameters during the standard and cool phases. A total of 93 participants were included. The number of IDH episodes during the standard and cool phases were 3.3 ± 2.8 and 2.0 ± 2.2 per patient respectively (P < 0.001). Other hemodynamic parameters including lowest intradialytic mean arterial pressure were significantly increased with ICD. We found that there was a high baseline rate of feeling cold among all participants and it increased after the implementation of ICD; however, the dropout rate was approximately 5%. ICD is an effective tool to decrease the frequency of IDH in the HD population and we provide a pragmatic, real‐world approach to implement this technique.
Inflammasome activation during spontaneous preterm labor with intra‐amniotic infection or sterile intra‐amniotic inflammation
Authors: Gomez‐Lopez Nardhy , Romero Roberto , Panaitescu Bogdan , Leng Yaozhu , Xu Yi , Tarca Adi L. , Faro Jonathan , Pacora Percy , Hassan Sonia S. , Hsu Chaur‐Dong 
Published: September 2018

ProblemThe inflammasome is implicated in the mechanisms that lead to spontaneous preterm labor (PTL). However, whether there is inflammasome activation in the amniotic cavity of women with PTL and intra‐amniotic infection (IAI) or sterile intra‐amniotic inflammation (SIAI) is unknown.Method of studyAmniotic fluid samples were collected from women with PTL who delivered at term (n = 31) or preterm without IAI or SIAI (n = 35), with SIAI (n = 27), or with IAI (n = 17). As a readout of inflammasome activation, extracellular ASC (apoptosis‐associated speck‐like protein containing a CARD) was measured in amniotic fluid by ELISA and the expression of ASC, caspase‐1, and interleukin (IL)‐1β was detected in the chorioamniotic membranes by multiplex immunofluorescence. Acute inflammatory responses in amniotic fluid and the placenta were also evaluated.Results(a) Amniotic fluid concentrations of ASC and IL‐6 were higher in women with PTL and IAI or SIAI than in those who delivered preterm or at term without intra‐amniotic inflammation; (b) amniotic fluid concentrations of ASC and IL‐6 were lower in women with PTL and SIAI than in those with IAI; (c) there was a significant nonlinear correlation between ASC and IL‐6 amniotic fluid concentrations; (d) the expression of inflammasome‐related proteins (ASC, caspase‐1, and IL‐1β) in the chorioamniotic membranes was increased in women with PTL and IAI or SIAI than in those who delivered preterm or at term without intra‐amniotic inflammation; (e) inflammasome activation in the chorioamniotic membranes was weaker in women with PTL and SIAI than in those with IAI; (f) women with PTL and IAI had elevated amniotic fluid white blood cell counts compared to those without this clinical condition; and (g) severe acute placental inflammatory lesions were observed in women with PTL and IAI and in a subset of women with PTL and SIAI.ConclusionInflammasome activation occurs in the settings of intra‐amniotic infection and sterile intra‐amniotic inflammation during spontaneous preterm labor.
Guns and the American Psyche
Authors: Merritt Dennis L. 
Published: September 2018

AbstractWhat is missing from most analyses of the gun crisis in America is an archetypal perspective. Archetypically, the Constitution is in the domain of the Bible in terms of it being the equivalent of a sacred text for Americans, making the Second Amendment a revered text for gun enthusiasts. It enshrines the insidious concept that people can rise up in armed resistance to an oppressive force, including the US government. The Minuteman is an archetypal mythic image in the American collective unconscious for the Second Amendment. A gun confers wakan (Sioux), sacred power, upon its possessor, allowing them to wield in an instant the archetype of death. This moves conflicts into the archetypal categories of good‐vs‐evil and black‐and‐white, circumventing the system of laws upon which our country is based and averting the dialogue upon which a democracy depends. The cowboy is another mythic image, the lonely gun‐toting individual who fought off beasts and savages to tame the Wild West. The very concept of America as “a shining city on the hill” that inspired our Puritan (archetypal image) ancestors is from the Book of Revelation in the Bible. They were not averse to using guns to exterminate the “heathen savages” they encountered. The arsenal of guns in America amplifies growing tensions around income inequality, increasing corporate power and deteriorating racial relations and inner city conditions.