bluuebunny/crossref_metadata_2025 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

Denileukin 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 Statement

Regulatory 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

Background

Late 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.

Methods

In 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.

Results

Transgene 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.

Conclusions

Comparison 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

Pitch 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

Delta 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.
Regulatory cocktail for dopaminergic neurons in a protovertebrate identified by whole-embryo single-cell transcriptomics
Authors: Horie Takeo , Horie Ryoko , Chen Kai , Cao Chen , Nakagawa Masashi , Kusakabe Takehiro G. , Satoh Noriyuki , Sasakura Yasunori , Levine Michael
Published: September 2018

The CNS of the protovertebrate Ciona intestinalis contains a single cluster of dopaminergic (DA) neurons, the coronet cells, which have been likened to the hypothalamus of vertebrates. Whole-embryo single-cell RNA sequencing (RNA-seq) assays identified Ptf1a as the most strongly expressed cell-specific transcription factor (TF) in DA/coronet cells. Knockdown of Ptf1a activity results in their loss, while misexpression results in the appearance of supernumerary DA/coronet cells. Photoreceptor cells and ependymal cells are the most susceptible to transformation, and both cell types express high levels of Meis. Coexpression of both Ptf1a and Meis caused the wholesale transformation of the entire CNS into DA/coronet cells. We therefore suggest that the reiterative use of functional manipulations and single-cell RNA-seq assays is an effective means for the identification of regulatory cocktails underlying the specification of specific cell identities.
Biomarker Identification by Feature Wrappers
Authors: Xiong Momiao , Fang Xiangzhong , Zhao Jinying
Published: September 2018

Gene expression studies bridge the gap between DNA information and trait information by dissecting biochemical pathways into intermediate components between genotype and phenotype. These studies open new avenues for identifying complex disease genes and biomarkers for disease diagnosis and for assessing drug efficacy and toxicity. However, the majority of analytical methods applied to gene expression data are not efficient for biomarker identification and disease diagnosis. In this paper, we propose a general framework to incorporate feature (gene) selection into pattern recognition in the process to identify biomarkers. Using this framework, we develop three feature wrappers that search through the space of feature subsets using the classification error as measure of goodness for a particular feature subset being “wrapped around”: linear discriminant analysis, logistic regression, and support vector machines. To effectively carry out this computationally intensive search process, we employ sequential forward search and sequential forward floating search algorithms. To evaluate the performance of feature selection for biomarker identification we have applied the proposed methods to three data sets. The preliminary results demonstrate that very high classification accuracy can be attained by identified composite classifiers with several biomarkers.
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.]
Random Monoallelic Expression of Three Genes Clustered within 60 kb of Mouse t Complex Genomic DNA
Authors: Sano Yuri , Shimada Tokihiko , Nakashima Hiroshi , Nicholson Rhonda H. , Eliason James F. , Kocarek Thomas A. , Ko Minoru S.H.
Published: September 2018

Mammals achieve gene dosage control by (1) random X-chromosome inactivation in females, (2) parental origin-specific imprinting of selected autosomal genes, and (3) random autosomal inactivation. Genes belonging to the third category of epigenetic phenomenon are just now emerging, with only six identified so far. Here we report three additional genes, Nubp2, Igfals, and Jsap1, that show 50%-methylated CpG sites by Southern blot analyses and primarily monoallelic expression in single-cell allele-specific RT-PCR analysis of bone marrow stromal cells and hepatocytes. Furthermore, we show that, in contrast to X inactivation, alleles can switch between active and inactive states during the formation of daughter cells. These three genes are the first in their category to exist as a tight cluster, in the proximal region of mouse chromosome 17, providing a thus far unique example of a region of autosomal random monoallelic expression.
Temperature-Modulated Array High-Performance Liquid Chromatography
Authors: Premstaller Andreas , Xiao Wenzhong , Oberacher Herbert , O'Keefe Matthew , Stern David , Willis Thomas , Huber Christian G. , Oefner Peter J.
Published: September 2018

Using novel monolithic poly(styrene-divinylbenzene) capillary columns with an internal diameter of 0.2 mm, we demonstrate for the first time the feasibility of constructing high-performance liquid chromatography arrays for the detection of mutations by heteroduplex analysis under partially denaturing conditions. In one embodiment, such an array can be used to analyze one sample simultaneously at different temperatures to maximize the detection of mutations in DNA fragments containing multiple discrete melting domains. Alternatively, one may inject different samples onto columns kept at the same effective temperature. Further improvements in throughput can be obtained by means of laser-induced fluorescence detection and the differential labeling of samples with up to four different fluorophores. Major advantages of monolithic capillary high-performance liquid chromatographic arrays over their capillary electrophoretic analogs are the chemical inertness of the poly(styrene-divinylbenzene) stationary phase, the physical robustness of the column bed due to its covalent linkage to the inner surface of the fused silica capillary, and the feasibility to modify the stationary phase thereby allowing the separation of compounds not only on the principle of size exclusion, but also adsorption, distribution, and ion exchange. Analyses times are on the order of a few minutes and turnaround time is extremely short as there is no need for the replenishment of the separation matrix between runs.
Crystal Structure of (E)-2-(3,3,3-trifluoroprop-1-en-1-yl)aniline
Authors: Kubono Koji , Tani Keita , Omote Masaaki , Ogawa Futa , Matsumoto Taisuke
Published: September 2018

The molecule of the title compound, C9H8F3N, adopts an E configuration with respect to the C=C double bond. The dihedral angle between the benzene ring and the prop-1-enyl group is 25.4 (3)°. In the crystal, molecules are linked via pairs of N—H...F hydrogen bonds into inversion dimers with an R
2
2(16) ring motif. The dimers are linked by C—H...N hydrogen bonds, forming a ribbon structure along the b-axis direction. The ribbons are linked by N—H...π and C—H...π interactions, generating a three-dimensional network.
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

Purpose

The 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/approach

To 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.

Findings

Results show positive emotional states, both personal and job-related, to positively and partially mediate the HRM–contextual performance relationship.

Research limitations/implications

Theoretically, 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 implications

Support is provided for HRM approaches which are more progressive than remedial in nature.

Originality/value

Emotions 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

Purpose

While 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/approach

A 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.

Findings

The 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 implications

The 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/value

This 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

Intradialytic 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

Problem

The 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 study

Amniotic 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.

Conclusion

Inflammasome 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

What 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.
Quantifying the lumbar spine movements of surgeons during surgical lists in a teaching hospital
Authors: Wartski Michelle , Williams Cylie M. , Broughton Nigel S. , Bowles Kelly‐Ann
Published: September 2018

Background

Low back pain (LBP) is a common occupational musculoskeletal complaint among health professionals. No research has quantified lumbar movement patterns in the surgical workplace, identifying ‘at risk’ behaviours with objective measures. This project aimed to identify lumbar movement patterns and change in LBP of surgeons and surgical trainees during a surgical list.

Methods

Surgeons or surgical trainees were recruited in a tertiary metropolitan hospital. Low back movements were quantified in real time via a monitoring system. This measured three‐dimensional movement, velocity, acceleration and orientation to gravity during a typical theatre session. Pre‐ and post‐surgery LBP, or low back injury measures of functional disability were quantified using the Oswestry disability index. Mean (standard deviation) and median (interquartile range) low back movement patterns were described. A Wilcoxon signed‐rank test determined differences in LBP recorded from beginning to end of recording periods.

Results

Participants (n = 28) recorded data for a mean (standard deviation) of 6.1 (2.2) h. On average, 27.7 lumbar flexion events were recorded per monitoring session, with flexion movements held for >30 s an average of 5.6 times. Many of the flexion events were considered low range (between 20° and 40°) with an average of 19.1 events per session. Orthopaedic trainees recorded the highest average of lumbar and sustained lumbar flexions per hour (4.13 times). LBP significantly increased over the work day (z = −2.53, P = 0.012).

Conclusion

This study provides a base for the understanding of low back movement patterns during surgery. This data may be useful in helping surgeons to identify their ‘high risk’ movements and prevent low back symptoms.
Resistance mechanism of the oncogenic β3‐αC deletion mutation in BRAF kinase to dabrafenib and vemurafenib revealed by molecular dynamics simulations and binding free energy calculations
Authors: Niu Yuzhen , Zhang Yan , Yao Xiaojun
Published: September 2018

BRAF kinase is an essential target for anti‐cancer drug development. Emergence of the β3‐αC loop deletion mutation (ΔNVTAP) in BRAF kinase frequently occurred in human cancers seriously compromises the therapeutic efficacy of some BRAF kinase inhibitors, such as dabrafenib and vemurafenib. However, the mechanism of this resistance is still not well understood. In this study, the influence of the β3‐αC deletion mutation on the binding profiles of three BRAF kinase inhibitors (AZ628, dabrafenib, and vemurafenib) with BRAFV600E or BRAFΔNVTAP was explored by conventional molecular dynamics (MD) simulations and binding free energy calculations. The simulation results indicated that the β3‐αC deletion mutation enhances the flexibility of the αC helix and alters their conformations, which amplify the conformational entropy change (−TΔS) and weaken the interactions between the inhibitors and BRAF. The further per‐residue binding free energy decomposition analysis revealed that the ΔNVTAP mutation changed the contributions of a few key residues to the bindings of dabrafenib or vemurafenib, such as L57, L66, W83, C84, F135, G145, and F147, but did not have obvious impact on the contributions of these residues to AZ628. Our results provide valuable clues to understand the mechanisms of drug resistance conferred by the β3‐αC deletion mutation.
Titration and optimization trial for the initiation of insulin glargine 100 U/mL in patients with inadequately controlled type 2 diabetes on oral antidiabetic drugs
Authors: Seufert Jochen , Fritsche Andreas , Pscherer Stefan , Anderten Helmut , Borck Anja , Pegelow Katrin , Bramlage Peter , Pfohl Martin
Published: September 2018

For patients with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control, addition of basal insulin is recommended, but titration and optimization of basal insulin therapy in primary care is not well understood. We conducted an observational trial in 2470 patients with T2DM who initiated insulin glargine 100 U/L (Gla‐100) on top of oral antidiabetic drugs. Physicians were free to choose either a “Davies,” “Fritsche” or “individual” titration algorithm. We found that fasting blood glucose (FBG) and glycated haemoglobin (HbA1c) levels were effectively reduced by Gla‐100; 65.9% of patients achieved the primary endpoint (FBG ≤6.1 mmol/L (110 mg/dL) or an individual HbA1c target). There were no significant differences in efficacy and safety between the algorithms used. The mean FBG decreased by 3.2 mmol/L (59 mg/dL) over 12 months, while the mean HbA1c decreased by 15.3 mmol/mol (1.4%)%. From a starting dose of 11.7 U/d, the Gla‐100 dosage was 22.8 U/d at 12 months, with similar values in each group. Rates of hypoglycaemia were low and did not differ by titration algorithm. We conclude that Gla‐100 was effective at reducing FBG and HbA1c, independent of the titration algorithm, but observed that algorithms were inconsistently applied in clinical practice.
Transitional status and modifiable risk of frailty in Japanese older adults: A prospective cohort study
Authors: Doi Takehiko , Makizako Hyuma , Tsutsumimoto Kota , Nakakubo Sho , Kim Min‐Ji , Kurita Satoshi , Hotta Ryo , Shimada Hiroyuki
Published: September 2018

Aim

The purpose of the present study was to identify risk factors for physical frailty and to understand the transitional status of frailty.

Methods

The participants were 4676 older adults in the National Center for Geriatrics and Gerontology ‐ Study of Geriatric Syndromes. Physical frailty status was classified as robust, pre‐frail and frail at baseline and 4‐year follow up (mean follow up 47.9 ± 1.8 months). Data for demographic variables, medical conditions, fall, depressive symptoms and cognitive function were also collected. Multiple imputation was used to reduce selection bias and loss of information.

Results

Progression occurred from a robust to frail status in 52 participants (2.6%) and from pre‐frailty to frailty in 281 participants (12.0%). Mortality increased with frailty status at baseline: robust 46 (2.3%), pre‐frail 112 (4.8%) and frail 54 (15.6%). In logistic regression analysis, age (OR 1.10, 95% CI 1.06–1.13), sex (men; OR 0.67, 95% CI 0.46–0.95), body mass index (OR 1.06, 95% CI 1.01–1.12]), fall (OR 1.92, 95% CI 1.31–2.81), Geriatric Depression Scale (OR 1.15, 95% CI 1.08–1.22), Mini‐Mental State Examination (OR 0.87, 95% CI 0.82–0.93) and education (OR 0.91, 95% CI 0.85–0.98), were related with new incident frailty. Among participants in the pre‐frail class at baseline, exhaustion (OR 3.24, 95% CI 1.97–5.34), physical inactivity (OR 3.09, 95% CI 1.94–4.93), lower muscle strength (OR 3.77, 95% CI 2.35–6.03) and lower mobility (OR 2.54, 95% CI 1.57–4.10) were related to progression to frailty (all P < 0.05).

Conclusions

The results of the present prospective study provide key information on the transitional status of frailty and the risk factors for progression to frailty. A further study is required to determine the pathophysiological changes that underlie the transition to frailty. Geriatr Gerontol Int 2018; 18: 1562–1566.
‘Ripple’ effect on infant zBMI trajectory of an internet‐based weight loss program for low‐income postpartum women
Authors: Phelan S. , Hagobian T. A. , Ventura A. , Brannen A. , Erickson‐Hatley K. , Schaffner A. , Muñoz‐Christian K. , Mercado A. , Tate D. F.
Published: September 2018

Background

Weight loss interventions can have positive ‘ripple’ effects on untreated partners in the home, but ripple effects on infants are unknown.

Objective

To examine whether a 12‐month internet‐based weight loss intervention for postpartum mothers had a positive ripple effect on participants' infants.

Methods

A 12‐month cluster randomized, assessor‐blind, clinical trial enrolling 371 postpartum women at 12 Women, Infants, Children clinics in CA. Clinics were randomized to standard Women, Infants, Children or an internet‐based weight loss intervention for mothers.

Results

A total of 333 of the 371 (89.8%) mothers assented for infant participation. Infants were 5.3 ± 3.2 months; 75.9% were Hispanic and 64% were breastfeeding. Infant retention was 272/333 (82.7%) at 6 months post enrollment and 251/333 (75.3%) at 12 months post enrollment. In intent‐to‐treat analysis, a significant interaction between group and time was observed (p = 0.008) with the offspring of intervention mothers exhibiting lower zBMI change from study entry through 6 months (0.23 [CI, 0.03, 0.44] vs. 0.65 [0.50, 0.79] zBMI change, respectively;p = 0.001) but was not significant through 12 months (p = 0.16). Regardless of group, maternal reports at the final assessment indicated that infants (aged =17.2 ± 3.4 months) consumed sweetened beverages (0.93 ± 1.5/week), juice (2.0 ± 1.4/day), ‘junk food’ (7.8 ± 5.4/week) and fast food (2/month), and 46.7% of the infants had a TV in their bedroom.

Conclusions

An internet‐based weight loss program for low‐income, postpartum mothers had a positive ‘ripple’ effect on the zBMI of infants in the home during the first 6 months of treatment.
Species divergence and maintenance of species cohesion of three closely related Primula species in the Qinghai–Tibet Plateau
Authors: Ren Guangpeng , Mateo Rubén G. , Guisan Antoine , Conti Elena , Salamin Nicolas
Published: September 2018

Aim

Understanding the relative roles of geography and ecology in driving speciation, population divergence and maintenance of species cohesion is of great interest to molecular ecology. Closely related species that are parapatrically distributed in mountainous areas provide an ideal model to evaluate these key issues, especially when genomic data are analyzed within a spatially and ecologically explicit context. Here, we used three closely related species of Primula that occur in the Himalayas, the Hengduan Mountains and north‐east Qinghai–Tibet Plateau (QTP) to examine spatial and ecological effects on interspecific divergence and maintenance of species cohesion.

Location

Himalayas, the Hengduan Mountains and north‐east QTP.

Methods

We used genomic data for 770 samples of the three species using double‐digest restriction site‐associated DNA (ddRAD) sequencing and combined approximate Bayesian computation (ABC) modeling, generalized linear mixed modeling (GLMM) and niche‐based species distribution modeling (SDM).

Results

The three species are clearly delimited by the RADseq data. Further ABC modeling indicates that Primula tibetica diverged first followed by a later divergence between Primula nutans and Primula fasciculata. The time frames of the divergences among the three species coincide with the uplifts of the Hengduan Mountains and the northern QTP during the late Miocene and Pliocene followed by a long period of founder events. SDMs indicate that the three species might have survived in different refugia during glaciations and came into secondary contact during the postglacial expansions but with no significant introgression. Finally, GLMM suggests that both the geographical and ecological factors play roles in population differentiation in P. fasciculata and P. tibetica, while for P. nutans, geography is the major driver of genomic variation. The different roles played by geographical and ecological factors in the three species may have affected the maintenance of species cohesion.

Main conclusion

Our results provide insights of unprecedented details into the start and maintenance of interspecific divergence in the context of changing environments in mountains. Our findings highlight the significance of combining population genomics with environmental data when evaluating the effects of geography and ecology on interspecific divergence and maintenance of closely related species.
The instructor's gaze guidance in video lectures improves learning
Authors: Wang Hongyan , Pi Zhongling , Hu Weiping
Published: September 2018

Instructor behaviour is known to affect learning performance, but it is unclear which specific instructor behaviours can optimize learning. We used eye‐tracking technology and questionnaires to test whether the instructor's gaze guidance affected learners' visual attention, social presence, and learning performance, using four video lectures: declarative knowledge with and without the instructor's gaze guidance and procedural knowledge with and without the instructor's gaze guidance. The results showed that the instructor's gaze guidance not only guided learners to allocate more visual attention to corresponding learning content but also increased learners' sense of social presence and learning. Furthermore, the link between the instructor's gaze guidance and better learning was especially strong for participants with a high sense of social connection with the instructor when they learned procedural knowledge. The findings lead to a strong recommendation for educational practitioners: Instructors should provide gaze guidance in video lectures for better learning performance.
On‐line discrimination of storage shelf‐life and prediction of post‐harvest quality for strawberry fruit by visible and near infrared spectroscopy
Authors: Shen Fei , Zhang Bin , Cao Chongjiang , Jiang Xuesong
Published: September 2018

Quick assessment of storage time is important for the guarantee of fruit shelf‐life. On‐line discrimination of refrigerated storage time and prediction of post‐harvest quality for strawberry fruit was carried out by visible and near‐infrared (Vis/NIR) spectroscopy. For the classification of samples with storage time of 1, 3, 5, and 7 days, partial least square discriminant analysis (PLS‐DA) achieved correct classified rates of 93.3–97.4% in prediction based on selected wavelengths obtained by competitive adaptive reweighted sampling (CARS) at speeds of 0.05, 0.10, and 0.15 m/s. Moreover, for prediction of soluble solids content (SSC) in strawberry, the determination coefficient (rp2), root mean square error of prediction (RMSEP), and RPD value obtained by PLS coped with CARS at fruit moving speed of 0.10 m/s was 0.733, 0.699 °Brix and 1.96, respectively. Overall, this study indicates that Vis–NIR spectroscopy offers the potential as an on‐line tool for quality assurance of strawberry fruit.

Practical applications

Visible and near‐infrared (Vis/NIR) spectroscopy is a very attractive technique for nondestructive evaluation of quality of food products. Strawberry has an extremely short shelf‐life which is estimated to be less than 5 days. Rapid identification its postharvest storage time is essential for the evaluation of its shelf‐life. Based on the results reported here, Vis–NIR has the potential for on‐line monitoring of postharvest storage time and post‐harvest quality for strawberry fruit in real situation.
A systematic review of cognitive behavioural therapy for anxiety in adults with intellectual disabilities
Authors: Dagnan D. , Jackson I. , Eastlake L.
Published: September 2018

Background

Anxiety disorders have high prevalence in people with intellectual disabilities. In populations without intellectual disabilities, cognitive behavioural therapy is a first line psychological therapy for these presentations. There is no existing review of the range of methods and outcomes from intervention studies in this area.

Method

A systematic review was carried out following guidance in the Cochrane handbook for systematic reviews of interventions.

Results

Nineteen studies were identified. The majority of reports were descriptive case studies; the most frequently described presentations were non‐specific anxiety disorders and post‐traumatic stress disorder; the most frequently described cognitive techniques were psycho‐education and interventions directly aimed at thoughts and beliefs and most studies reported positive outcomes, although the better controlled studies tended to report less comprehensive impacts.

Conclusions

A range of presentations have been described although the area is still at a primarily descriptive stage. We discuss intervention structures and approaches that require further research.
Procedural management of rhinophyma: A comprehensive review
Authors: Krausz Aimee E. , Goldberg David J. , Ciocon David H. , Tinklepaugh Adam J.
Published: September 2018

Background

Rhinophyma is a cosmetically deforming disease characterized by nodular overgrowth of the lower 2/3 of the nose and is considered the end stage of acne rosacea.

Aims

Review the spectrum of procedural techniques for treatment of rhinophyma with a focus on the advantages and disadvantages of each modality.

Methods

A comprehensive literature search was conducted using the search terms “rhinophyma,” “treatment,” and “surgery” in PubMed. Case reports, case series, and small retrospective trials using procedural techniques for management of rhinophyma were included for review. Animal studies, non‐English articles, and reports of medical treatment of rhinophyma were excluded.

Results

There are currently no prospective, randomized controlled studies evaluating procedural management of rhinophyma. The most commonly employed treatments include scalpel excision, resection with heated knives, dermabrasion, electrosurgery and lasers, specifically carbon dioxide (CO2) and erbium:yttrium‐aluminum‐garnet (Er:YAG). The main complication associated with complete excision of rhinophymatous tissue is excessive scarring. To correct for this adverse effect, partial or tangential excision with preservation of underlying adnexal structures is now the accepted technique, irrespective of the chosen modality.

Conclusion

There is no accepted gold standard for management of rhinophyma, and each modality succeeds in maintaining hemostasis, reducing scarring and achieving satisfactory cosmesis to different degrees. There is a conflicting data on the theoretical risk of recurrence with partial excision due to incomplete removal of tissue. Further studies evaluating this risk and alternate methods of prevention are required.