bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect susceptibility to developmental polychlorinated biphenyl exposure in mice: Relevance to studies of human neurological disorders
Authors: Klinefelter Kelsey , Hooven Molly Kromme , Bates Chloe , Colter Breann T. , Dailey Alexandra , Infante Smitha Krishnan , Kania-Korwel Izabela , Lehmler Hans-Joachim , López-Juárez Alejandro , Ludwig Clare Pickering , Curran Christine Perdan
Published: September 2017

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain a human health concern with the discovery of new sources of contamination and ongoing bioaccumulation and biomagnification. Children exposed during early brain development are at highest risk of neurological deficits, but there is some evidence that high PCB exposure in adults increases the risk of Parkinson’s disease. Our previous studies found allelic differences in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) affect susceptibility to developmental PCB exposure, resulting in cognitive deficits and motor dysfunction. High-affinityAhrbCyp1a2(-/-)mice were most susceptible compared with poor-affinityAhrdCyp1a2(-/-)and wild typeAhrbCyp1a2(+/+)mice. Our follow-up studies assessed biochemical, histological and gene expression changes to identify the brain regions and pathways affected. We also measured PCB and metabolite levels in multiple tissues to determine if genotype altered toxicokinetics. We found evidence of AHR-mediated immune suppression with reduced thymus and spleen weights and significantly reduced thyroxine at P14. In the brain, the greatest changes were seen in the cerebellum where a foliation defect was over-represented inCyp1a2(-/-)mice. In contrast, we found no difference in tyrosine hydroxylase immuno-staining in the striatum. Gene expression patterns varied across the three genotypes, but there was clear evidence of AHR activation. Distribution of parent PCB congeners also varied by genotype with strikingly high levels of PCB 77 in poor-affinityAhrdCyp1a2(-/-)whileAhrbCyp1a2(+/+)mice effectively sequestered coplanar PCBs in the liver. Together, our data suggest that the AHR pathway plays a role in developmental PCB neurotoxicity, but we found little evidence that developmental exposure is a risk factor for Parkinson’s disease.
A distributed algorithm to maintain and repair the trail networks of arboreal ants
Authors: Chandrasekhar Arjun , Gordon Deborah M. , Navlakha Saket
Published: September 2017

We study how the arboreal turtle ant (Cephalotes goniodontus) solves a fundamental computing problem: maintaining a trail network and finding alternative paths to route around broken links in the network. Turtle ants form a routing backbone of foraging trails linking several nests and temporary food sources. This species travels only in the trees, so their foraging trails are constrained to lie on a natural graph formed by overlapping branches and vines in the tangled canopy. Links between branches, however, can be ephemeral, easily destroyed by wind, rain, or animal movements. Here we report a biologically feasible distributed algorithm, parameterized using field data, that can plausibly describe how turtle ants maintain the routing backbone and find alternative paths to circumvent broken links in the backbone. We validate the ability of this probabilistic algorithm to circumvent simulated breaks in synthetic and real-world networks, and we derive an analytic explanation for why certain features are crucial to improve the algorithm’s success. Our proposed algorithm uses fewer computational resources than common distributed graph search algorithms, and thus may be useful in other domains, such as for swarm computing or for coordinating molecular robots.
Fast and Accurate Genomic Analyses using Genome Graphs
Authors: Rakocevic Goran , Semenyuk Vladimir , Spencer James , Browning John , Johnson Ivan , Arsenijevic Vladan , Nadj Jelena , Ghose Kaushik , Suciu Maria C. , Ji Sun-Gou , Demir Gülfem , Li Lizao , Toptaş Berke Ç. , Dolgoborodov Alexey , Pollex Björn , Spulber Iosif , Glotova Irina , Kómár Péter , Stachyra Andrew , Li Yilong , Popovic Milos , Lee Wan-Ping , Källberg Morten , Jain Amit , Kural Deniz
Published: September 2017

The human reference genome serves as the foundation for genomics by providing a scaffold for alignment of sequencing reads, but currently only reflects a single consensus haplotype, which impairs read alignment and downstream analysis accuracy. Reference genome structures incorporating known genetic variation have been shown to improve the accuracy of genomic analyses, but have so far remained computationally prohibitive for routine large-scale use. Here we present a graph genome implementation that enables read alignment across 2,800 diploid genomes encompassing 12.6 million SNPs and 4.0 million indels. Our Graph Genome Pipeline requires 6.5 hours to process a 30x coverage WGS sample on a system with 36 CPU cores compared with 11 hours required by the GATK Best Practices pipeline. Using complementary benchmarking experiments based on real and simulated data, we show that using a graph genome reference improves read mapping sensitivity and produces a 0.5% increase in variant calling recall, or about 20,000 additional variants being detected per sample, while variant calling specificity is unaffected. Structural variations (SVs) incorporated into a graph genome can be genotyped accurately under a unified framework. Finally, we show that iterative augmentation of graph genomes yields incremental gains in variant calling accuracy. Our implementation is a significant advance towards fulfilling the promise of graph genomes to radically enhance the scalability and accuracy of genomic analyses.
MatClassRSA: A Matlab toolbox for M/EEG classification and visualization of proximity matrices
Authors: Wang Bernard C. , Norcia Anthony M. , Kaneshiro Blair
Published: September 2017

MatClassRSA is a Matlab toolbox that performs M/EEG classification and produces various visualizations of the resulting confusion matrices. This toolbox is aimed toward cognitive neuroscience researchers who wish to apply classification-style analyses to repeated trials of data. The functionalities of the toolbox fall into three categories: (1) M/EEG classification, (2) computation of Representational Dissimilarity Matrices (RDMs) from confusion or other proximity matrices, and (3) clustering and tree visualizations of RDMs. MatClassRSA combines out-of-the-box functionality with a variety of customization options. Usage of the toolbox requires only a high-level understanding of machine learning and the ability to call Matlab functions from scripts.
The Wild-type and Gain-of-function Mutant p53 Enhance p300 Autoacetylation through Conformational Switching
Authors: Kaypee Stephanie , Ghosh Raka , Sahadevan Smitha Asoka , Patil Shilpa , Shasmal Manidip , Ghosh Piya , Roy Neeladri , Sengupta Jayati , Roy Siddhartha , Kundu Tapas K.
Published: September 2017

The transcriptional coactivator p300 is essential for p53 transactivation, although its precise mechanism remains unclear. We report that, p53 allosterically activates the acetyltransferase activity of p300 through the enhancement of p300 autoacetylation. Cryo-electron microscopy revealed that the domain organization of p300 is substantially altered upon binding of p53, suggesting that a structural switch may underpin the activation. Acetylated p300 accumulates near the transcription start sites accompanied by a similar enrichment of activating histone marks near those sites. Disruption of p53-p300 interaction by a site-directed peptide inhibitor abolished autoacetylated p300-mediated enhanced histone acetylation, suggesting a crucial role played by the allosteric activation in p53-mediated gene regulation. Gain-of-function mutant p53, known to impart aggressive proliferative properties in tumor cells, also activate p300 autoacetylation. The same peptide abolished many of the gain-of-functions of mutant p53 as well. We conclude that allosteric activation of p300 by p53 underpins gene regulation by p53. Reversal of gain-of-function properties of mutant p53 suggests that molecules targeting the p53-p300 interface may be good candidates for anti-tumor drugs.
Approximate Bayesian computation reveals the importance of repeated measurements for parameterising cell-based models of growing tissues
Authors: Kursawe Jochen , Baker Ruth E. , Fletcher Alexander G.
Published: September 2017

The growth and dynamics of epithelial tissues govern many morphogenetic processes in embryonic development. A recent quantitative transition in data acquisition, facilitated by advances in genetic and live-imaging techniques, is paving the way for new insights to these processes. Computational models can help us understand and interpret observations, and then make predictions for future experiments that can distinguish between hypothesised mechanisms. Increasingly, cell-based modelling approaches such as vertex models are being used to help understand the mechanics underlying epithelial morphogenesis. These models typically seek to reproduce qualitative phenomena, such as cell sorting or tissue buckling. However, it remains unclear to what extent quantitative data can be used to constrain these models so that they can then be used to make quantitative, experimentally testable predictions. To address this issue, we perform anin silicostudy to investigate whether vertex model parameters can be inferred from imaging data, and explore methods to quantify the uncertainty of such estimates. Our approach requires the use of summary statistics to estimate parameters. Here, we focus on summary statistics of cellular packing and of laser ablation experiments, as are commonly reported from imaging studies. We find that including data from repeated experiments is necessary to generate reliable parameter estimates that can facilitate quantitative model predictions.
Genomic signature of experimental adaptation ofStaphylococcus aureusto a natural combination of insect antimicrobial peptides
Authors: Makarova Olga , Johnston Paul , Rodriguez-Rojas Alexandro , el-Shazely Baydaa , Moreno Morales Javier , Rolff Jens
Published: September 2017

Antimicrobial peptides are highly conserved immune effectors across the tree of life and are employed as combinations. In the beetleTenebrio molitor, a defensin and a coleoptericin are highly expressedin vivoafter inoculation withS. aureus. The defensin displays strongin vitroactivity but no survival benefitin vivo. The coleoptericin provides a survival benefit in vivo, but no activity in vitro. To investigate this paradox we experimentally evolvedS. aureusto increased resistance against the defensin and a combination of the defensin and coleoptericin. Genome re-sequencing showed that resistance was associated with mutations in either theytrornsaoperons, in both AMP treatments. Strains with these mutations show longer lag phases, slower Vmax andnsamutants reach lower final population sizes. Mutations inrpoBwere showed a further increase in the lag phase innsamutants but not inytrmutants. In contrast, final MICs do not segregate by mutation. All resistant lines display AMP but not antibiotic cross-resistance. Costly resistance against AMPs readily evolves for an individual AMP as well as a naturally occurring combinationin vitroand provides broad protection against AMPs. Such non-specific resistance could result in strong selection on host immune systems that rely on cocktails of AMPs.
Uncoordinated centrosome duplication cycle underlies the instability of non-diploid states in mammalian somatic cells
Authors: Yaguchi Kan , Matsui Ryo , Yamamoto Takahiro , Tsukada Yuki , Shibanuma Atsuko , Kamimura Keiko , Koda Toshiaki , Uehara Ryota
Published: September 2017

In animals, somatic cells are usually diploid and are unstable when haploid for unknown reasons. In this study, by comparing isogenic human cell lines with different ploidies, we found frequent centrosome loss specifically in the haploid state, which profoundly contributed to haploid instability through monopolar spindle formation and subsequent mitotic defects. We also found that efficiency of centriole licensing and duplication, but not that of DNA replication, changes proportionally to ploidy level, causing gradual loss or frequent overduplication of centrioles in haploid and tetraploid cells, respectively. Centriole licensing efficiency seemed to be modulated by astral microtubules, whose development scaled with ploidy level, and artificial enhancement of aster formation in haploid cells restored centriole licensing efficiency to diploid levels. Haploid-specific centrosome loss was also observed in parthenogenetic mouse embryos. We propose that incompatibility between the centrosome duplication and DNA replication cycles arising from different scaling properties of these bioprocesses upon ploidy changes, underlies the instability of non-diploid somatic cells in mammals.

Yaguchi et al. show that a delay or acceleration of centriole licensing compromises the control of centrosome number in haploid or tetraploid human cells, respectively, suggesting a cellular basis of the instability of non-diploid somatic cells in mammals.
Individual nephron proteomes connect morphology and function in proteinuric kidney disease
Authors: Höhne Martin , Frese Christian K. , Grahammer Florian , Dafinger Claudia , Ciarimboli Giuliano , Butt Linus , Binz Julia , Hackl Matthias J. , Rahmatollahi Mahdieh , Kann Martin , Schneider Simon , Altintas Mehmet M. , Schermer Bernhard , Reinheckel Thomas , Göbel Heike , Reiser Jochen , Huber Tobias B. , Kramann Rafael , Seeger-Nukpezah Tamina , Liebau Max C. , Beck Bodo B. , Benzing Thomas , Beyer Andreas , Rinschen Markus M.
Published: September 2017

In diseases of many parenchymatous organs, heterogenous detoriation of individual functional units determines the clinical prognosis. However, the molecular characterization of these subunits remains a technological challenge that needs to be addressed in order to better understand pathological mechanisms. Sclerotic and proteinuric glomerular kidney disease is a frequent and heterogeneous disease which affects a fraction of nephrons, glomeruli and draining tubules, to variable extents, and for which no treatment exists. Here, we developed and applied an antibody-independent methodology to investigate heterogeneity of individual nephron segment proteomes from mice with proteinuric kidney disease. This “one-segment-one-proteome-approach” defines mechanistic connections between upstream (glomerular) and downstream (tubular) nephron segment populations. In single glomeruli from two different mouse models of sclerotic glomerular disease, we identified a coherent protein expression module consisting of extracellular matrix protein deposition (reflecting glomerular sclerosis), glomerular albumin (reflecting proteinuria) and LAMP1, a lysosomal protein. This module was associated with a loss of podocyte marker proteins. In an attempt to target this protein co-expression module, genetic ablation of LAMP1-correlated lysosomal proteases in mice could ameliorate glomerular damage. Furthermore, individual glomeruli from patients with genetic sclerotic and non-sclerotic proteinuric diseases demonstrated increased abundance of lysosomal proteins, in combination with a decreased abundance of the mutated gene products. Therefore, increased glomerular lysosomal load is a conserved key mechanism in proteinuric kidney diseases, and the technology applied here can be implemented to address heterogeneous pathophysiology in a variety of diseases at a sub-biopsy scale
Neural coding of fine-grained object knowledge in perirhinal cortex
Authors: Price Amy Rose , Bonner Michael F. , Peelle Jonathan E. , Grossman Murray
Published: September 2017

Over 40 years of research has examined the role of the ventral visual stream in transforming retinal inputs into high-level representations of object identity [1–6]. However, there remains an ongoing debate over the role of the ventral stream in coding abstract semantic content, which relies on stored knowledge, versus perceptual content that relies only on retinal inputs [7–12]. A major difficulty in adjudicating between these mechanisms is that the semantic similarity of objects is often highly confounded with their perceptual similarity (e.g., animate things are more perceptually similar to other animate things than to inanimate things). To address this problem, we developed a paradigm that exploits the statistical regularities of object colors while perfectly controlling for perceptual shape information, allowing us to dissociate lower-level perceptual features (i.e., color perception) from higher-level semantic knowledge (i.e., color meaning). Using multivoxel-pattern analyses of fMRI data, we observed a striking double dissociation between the processing of color information at a perceptual and at a semantic level along the posterior to anterior axis of the ventral visual pathway. Specifically, we found that the visual association region V4 assigned similar representations to objects with similar colors, regardless of object category. In contrast, perirhinal cortex, at the apex of the ventral visual stream, assigned similar representations to semantically similar objects, even when this was in opposition to their perceptual similarity. These findings suggest that perirhinal cortex untangles the representational space of lower-level perceptual features and organizes visual objects according to their semantic interpretations.
A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells
Authors: Ressa Anna , Bosdriesz Evert , de Ligt Joep , Mainardi Sara , Maddalo Gianluca , Prahallad Anirudh , Jager Myrthe , de la Fonteijne Lisanne , Fitzpatrick Martin , Groten Stijn , Altelaar A. F. Maarten , Bernards René , Cuppen Edwin , Wessels Lodewyk , Heck Albert J. R.
Published: September 2017

Intrinsic and/or acquired resistance represents one of the great challenges in targeted cancer therapy. A deeper understanding of the molecular biology of cancer has resulted in more efficient strategies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has also been observed in colorectal cancer patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block intrinsic resistance to BRAF inhibitors. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant colorectal cancer cells as a model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both known and novel responses. We primarily observe widespread upregulation of receptors tyrosine kinases and metabolic pathways upon BRAF inhibition. These findings point to mechanisms by which the drug-treated cells switch energy sources and enter a quiescent-like state as a defensive response, while additionally reactivating the MAPK pathway.
Successful optimization of CRISPR/Cas9-mediated defined point mutation knock-in using allele-specific PCR assays in zebrafish
Authors: Prykhozhij Sergey V. , Fuller Charlotte , Steele Shelby L. , Veinotte Chansey J. , Razaghi Babak , Robitaille Johane , McMaster Christopher , Shlien Adam , Malkin David , Berman Jason N.
Published: September 2017

Single-stranded oligodeoxynucleotides (ssODN) are donor templates for homology-directed repair-based knock-in of point mutations using CRISPR/Cas9. To optimize the efficiency of ssODN-based knock-ins in zebrafish, we developed allele-specific PCR (AS-PCR) assays for introducing point mutations intp53,cdh5andlmnaas case studies. In these point mutation strategies we introduced the codon mutations, sgRNA site mutations and restriction sites which can be detected by AS-PCR with the primers matching their respective alleles in combination with a common primer. We employed the anti-sense asymmetric oligo design as the main optimization as well as phosphorothioate oligo modification and also observed that proximity of the mutation site to the Cas9 cut site improves the efficiency when knock-ins into different genes were compared. We improved the efficiencies of twotp53knock-ins using anti-sense asymmetric ultramer oligos (126-nt in length with homology arms of 36 and 90 nucleotides, anti-sense to the sgRNA) by 3-10 fold, the optimizations which resulted in successful founders for bothtp53knock-ins with transmission rates of 20-40 %. The initially low knock-in efficiency fortp53mutants was likely due to the distance between the Cas9 cut site and mutations sincecdh5G767S knock-in located at the cut site had much higher founder identification and germline transmission rates. The phosphorothioate oligo modifications was used for a lamin A/C (lmna) knock-in strategy and it resulted in 40 % overall improvement in knock-in efficiency and greater knock-in consistency. We also determined that AS-PCR detected false-positive knock-ins which constituted 25-80 % of total in different strategies and developed a workflow to screen out the founders and F1 zebrafish carrying these undesirable modifications. In summary, we provide a complementary set of optimizations for CRISPR/Cas9-based ssODN knock-ins in zebrafish using a novel combination of methods.
Traditional NorwegianKveikYeasts: Underexplored DomesticatedSaccharomyces cerevisiaeYeasts
Authors: Preiss Richard , Tyrawa Caroline , van der Merwe George
Published: September 2017

Human activity has resulted in the domestication ofSaccharomyces cerevisiaeyeasts specifically adapted to beer production. While there is evidence beer yeast domestication was accelerated by industrialization of beer, there also exists a home-brewing culture in western Norway which has passed down yeasts referred to askveikfor generations. This practice has resulted in ale yeasts which are typically highly flocculant, phenolic off flavour negative (POF-), and exhibit a high rate of fermentation, similar to previously characterized lineages of domesticated yeast. Additionally,kveikyeasts are highly temperature tolerant, likely due to the traditional practice of pitching yeast into warm (>30 °C) wort. Here, we characterizekveikyeasts from 9 different Norwegian sources via PCR fingerprinting, phenotypic screens, lab-scale fermentations, and flavour metabolite analysis using HS-SPME-GC-MS. Genetic fingerprinting via interdelta PCR suggests thatkveikyeasts form a lineage distinct from other domesticated yeasts. Our analyses confirm thatkveikyeasts display hallmarks of domestication such as loss of 4-vinylguaiacol production and high flocculation, and show superior thermotolerance, ethanol tolerance, fermentation rate, and unique flavour metabolite production profiles in comparison to other ale strains, suggesting a broad industrial potential for this group of yeasts.
Cdt1 modulates kinetochore-microtubule attachment stabilization via an Aurora B kinase-dependent mechanism
Authors: Agarwal Shivangi , Smith Kyle Paul , Zhou Yizhuo , Suzuki Aussie , McKenney Richard J. , Varma Dileep
Published: September 2017

Robust kinetochore-microtubule (kMT) attachment is critical for accurate chromosome segregation. G2/M-specific depletion of human Cdt1 that localizes to kinetochores in an Ndc80 complex-dependent manner, leads to abnormal kMT attachments and mitotic arrest. This indicates an independent mitotic role for Cdt1 in addition to its prototypic function in DNA replication origin licensing. Here, we show that Cdt1 directly binds to microtubules (MTs). Endogenous or transiently expressed Cdt1 localizes to both mitotic spindle MTs and kinetochores. Deletion mapping of Cdt1 revealed that the regions comprising the middle and C-terminal winged-helix domains but lacking the N-terminal unstructured region was required for efficient MT-binding. Mitotic kinase Aurora B interacts with and phosphorylates Cdt1. Aurora B-phosphomimetic Cdt1 exhibited attenuated MT-binding and its cellular expression induced defective kMT attachments with a concomitant delay in mitotic progression. Thus we provide mechanistic insight into how Cdt1 affects overall kMT stability in an Aurora B kinase phosphorylation-dependent manner; which is envisioned to augment the MT-binding of the Ndc80 complex.

eTOC summary

• Cdt1 binds to microtubules

• The middle and the C-terminal winged-helix domains of Cdt1 are involved in MT-binding

• Aurora B Kinase phosphorylates Cdt1 and influences its MT-binding

• Aurora B-mediated Cdt1 phosphorylation is necessary for kMT stability and mitotic progression
Entering the era of conservation genomics: Cost-effective assembly of the African wild dog genome using linked long reads
Authors: Armstrong Ellie E. , Taylor Ryan W. , Prost Stefan , Blinston Peter , der Meer Esther van , Madzikanda Hillary , Mufute Olivia , Mandisodza Roseline , Stuelpnagel John , Sillero-Zubiri Claudio , Petrov Dmitri
Published: September 2017

A high-quality reference genome assembly is a valuable tool for the study of non- model organisms across disciplines. Genomic techniques can provide important insights about past population sizes, local adaptation, and even aid in the development of breeding management plans. This information can be particularly important for fields like conservation genetics, where endangered species require critical and immediate attention. However, funding for genomic-based methods can be sparse for conservation projects, as costs for general species management can consume budgets. Here we report the generation of high-quality reference genomes for the African wild dog (Lycaon pictus) at a low cost, thereby facilitating future studies of this endangered canid. We generated assemblies for three individuals from whole blood samples using the linked-read 10x Genomics Chromium system. The most continuous assembly had a scaffold N50 of 21 Mb, a contig N50 of 83 Kb, and completely reconstructed 95% of conserved mammalian genes as reported by BUSCO v2, indicating a high assembly quality. Thus, we show that 10x Genomics Chromium data can be used to effectively generate high-quality genomes of mammal species from Illumina short-read data of intermediate coverage (∼25-50x). Interestingly, the African wild dog shows a much higher heterozygosity than other species of conservation concern, possibly as a result of its behavioral ecology. The availability of reference genomes for non-model organisms will facilitate better genetic monitoring of threatened species such as the African wild dog. At the same time, they can help researchers and conservationists to better understand the ecology and adaptability of those species in a changing environment.
Reconstructing detailed line profiles of lamellar gratings from GISAXS patterns with a Maxwell solver
Authors: Soltwisch Victor , Fernández Herrero Analía , Pflüger Mika , Haase Anton , Probst Jürgen , Laubis Christian , Krumrey Michael , Scholze Frank
Published: September 2017

Laterally periodic nanostructures have been investigated with grazing-incidence small-angle X-ray scattering (GISAXS) by using the diffraction patterns to reconstruct the surface shape. To model visible light scattering, rigorous calculations of the near and far field by numerical solution of Maxwell's equations with a finite-element method are well established. The application of this technique to X-rays is still challenging, owing to the discrepancy between the incident wavelength and the finite-element size. This drawback vanishes for GISAXS because of the small angles of incidence, the conical scattering geometry and the periodicity of the surface structures, which allows a rigorous computation of the diffraction efficiencies with sufficient numerical precision. To develop metrology tools based on GISAXS, lamellar gratings with line widths down to 55 nm were produced by state-of-the-art electron-beam lithography and then etched into silicon. The high surface sensitivity of GISAXS in conjunction with a Maxwell solver allows the detailed reconstruction of the grating line shape for thick non-homogeneous substrates as well. The reconstructed geometric line-shape models are statistically validated by applying a Markov chain Monte Carlo sampling technique which reveals that GISAXS is able to reconstruct critical parameters like the widths of the lines with sub-nanometre uncertainty.
Selection of DNA Aptamer That Blocks the Fibrillogenesis of a Proteolytic Amyloidogenic Fragment of β2m
Authors: Fukasawa Kanon , Higashimoto Yuichiro , Ando Yukio , Motomiya Yoshihiro
Published: September 2017

Dialysis‐related amyloidosis (DRA) is a severe complication of hemodialysis that results in progressive destruction of bones and joints. Elevated concentrations of the β2‐microglobulin (β2m) level in the serum of subjects on hemodialysis promote the formation of amyloid fibrils in osteoarticular tissues. β2m lacking the N‐terminal six residues of the mature protein (ΔN6β2m) constitutes 25–30% of β2m in ex vivo DRA amyloid. Unlike full‐length wild‐type β2m, ΔN6β2m forms amyloid fibrils at neutral pH in vitro. However, the role of ΔN6β2m in DRA is, at present, poorly understood. In the present study, we screened novel phosphorothioate‐modified aptamers directed against ΔN6β2m using combinatorial chemistry in vitro. We identified 11 ΔN6β2m aptamers; among the identified aptamers, clone #2, #8, and #10 aptamers had higher binding affinity to ΔN6β2m than the others. Biolayer interferometry analysis revealed that KD values of clone #2, #8, and #10 aptamers were 56, 23, and 44 nM, respectively. Furthermore, the clone #8 aptamer inhibited fibril formation in a dose‐dependent manner, as assessed by Thioflavin T fluorescence assay. Fibrils formed from ΔN6β2m bind to Congo red, displaying changes in the absorbance spectrum of the dye characteristic of binding to amyloid fibrils, which was completely blocked by treatment with clone #8 aptamer. These results suggest the potential of ΔN6β2m aptamers as tools for elucidating co‐assembly mechanisms in amyloid formation.
Endoscopic sleeve gastroplasty and its application to China
Authors: Badurdeen Dilhana S , Kumbhari Vivek
Published: September 2017

Obesity is a burgeoning problem in China with potential for significant adverse economic and health consequences if not addressed. Unfortunately, the body mass index (BMI) targets used in the West are not applicable to China as Asians have visceral adiposity and thus develop complications of obesity at a lower BMI. Recent studies suggest using lower BMI targets for defining overweight and obesity and to qualify patients for bariatric surgery. Diet, exercise and pharmacology have been the foundation for treatment in those not meeting criteria for bariatric surgery, despite modest weight loss that is poorly sustained over time.

The large majority in China are averse to bariatric surgery and thus endoscopic bariatric therapy is emerging as an illustrious remedy to fill this gap. Of the current procedures available endoscopic sleeve gastroplasty has shown the most promise due to the significant and sustained weight loss it produces coupled with the ease of execution and lower cost.

The procedure is performed under general anesthesia using a full‐thickness endoscopic suturing device and patients are discharged the same day. The mean procedure time in experienced hands is 60 minutes. Due to the repetitive nature of the procedure, the learning curve is steep. Data thus far demonstrate total body weight loss to be 16–20% at 12 months. The safety profile is excellent with a low morbidity rate seen in the 3 000 procedures performed worldwide. Therefore, widespread dissemination in China is expected with the potential to help millions of obese patients.
Does previous caesarean section at full dilatation increase the likelihood of subsequent spontaneous preterm birth?
Authors: Cong Angela , de Vries Bradley , Ludlow Joanne
Published: September 2017

Background

There is emerging evidence that caesarean section at full dilatation is associated with an increased risk of subsequent spontaneous preterm birth.

Aim

To investigate the association between caesarean section at full dilatation and spontaneous preterm birth in subsequent pregnancies.

Materials and methods

This was a retrospective cohort study of women who had two consecutive births at Royal Prince Alfred Hospital, 1989–2015. Our main comparison group was women who had emergency caesarean sections during the first stage of labour. Secondary comparison groups were women who had elective caesarean sections, instrumental deliveries and unassisted vaginal deliveries. The primary outcome was spontaneous preterm birth (<37 weeks gestation) in a subsequent pregnancy.

Results

There were 2672 women who had an emergency caesarean section, with 2142 (80%) performed during the first stage of labour and 533 (20%) at full dilatation. The rates of spontaneous preterm birth in a subsequent pregnancy were 1.7% and 3.8%, respectively (odds ratio 2.2 (95%CI 1.3–3.8), P = 0.003). The hazard ratio for spontaneous onset of labour at any given gestation from 20 weeks until full term was 1.4 (95%CI 1.2–1.6) and did not change after adjusting for maternal age and body mass index.

Conclusion

There is a significantly higher rate of subsequent spontaneous preterm birth in women who had a caesarean section at full dilatation compared with women who had a caesarean section during the first stage of labour. Awareness of this as a risk factor may warrant referral to a high‐risk obstetric or preterm birth clinic.
Arterial catheterisation in neonates can result in severe ischaemic complications but does not impair long‐term extremity function
Authors: Deindl Philipp , Waldhör Thomas , Unterasinger Lukas , Berger Angelika , Keck Maike
Published: September 2017

Aim

We evaluated the incidence of arterial catheterisation and analysed the risk factors and the extent and outcome of ischaemic complications in neonates.

Methods

This was a retrospective cohort study of 1506 neonates admitted to two, ten‐bed neonatal intensive care units (NICUs) at the Medical University of Vienna, Austria, between 1 January 2011 and 31 December 2014. Medical charts, daily reports and photo documentation were reviewed for arterial catheterisation and ischaemic complications. Patients with severe ischaemic complications were followed up to evaluate extremity function, scaring and cosmetic results.

Results

There were 542 arterial catheterisations in 485 patients, including 275 born below 28 weeks, which resulted in severe complications in 19 of 485 (4%) patients. Three died before follow‐up. Patients with complications had a significantly lower birthweight, lower postmenstrual age and higher rates of intracranial haemorrhage, retinopathy of prematurity and necrotising enterocolitis. They had also undergone multiple arterial catheterisations more often, needed longer inotropic support and had longer NICU stays than patients without complications. Extremity function was unimpaired in ten of 16 patients with severe ischaemic complications.

Conclusion

Severe ischaemic complications in neonates following arterial catheterisation were rare events, but could cause devastating damage. Most patients didn't show impaired extremity function at follow‐up.
Chemokine (C‐X‐C motif) ligand 1 is a myokine induced by palmitate and is required for myogenesis in mouse satellite cells
Authors: Masuda S. , Tanaka M. , Inoue T. , Ohue‐Kitano R. , Yamakage H. , Muranaka K. , Kusakabe T. , Shimatsu A. , Hasegawa K. , Satoh‐Asahara N.
Published: September 2017

Aim

The functional significance of the myokines, cytokines and peptides produced and released by muscle cells has not been fully elucidated. The purpose of this study was to identify a myokine with increased secretion levels in muscle cells due to saturated fatty acids and to examine the role of the identified myokine in the regulation of myogenesis.

Methods

Human primary myotubes and mouse C2C12 myotubes were used to identify the myokine; its secretion was stimulated by palmitate loading. The role of the identified myokine in the regulation of the activation, proliferation, differentiation and self‐renewal was examined in mouse satellite cells (skeletal muscle stem cells).

Results

Palmitate loading promoted the secretion of chemokine (C‐X‐C motif) ligand 1 (CXCL1) in human primary myotubes, and it also increased CXCL1 gene expression level in C2C12 myotubes in a dose‐ and time‐dependent manner. Palmitate loading increased the production of reactive oxygen species along with the activation of nuclear factor‐kappa B (NF‐κB) signalling. Pharmacological inhibition of NF‐κB signalling attenuated the increase in CXCL1 gene expression induced by palmitate and hydrogen peroxide. Palmitate loading significantly increased CXC receptor 2 gene expression in undifferentiated cells. CXCL1 knockdown attenuated proliferation and myotube formation by satellite cells, with reduced self‐renewal. CXCL1 knockdown also significantly decreased the Notch intracellular domain protein level.

Conclusion

These results suggest that secretion of the myokine CXCL1 is stimulated by saturated fatty acids and that CXCL1 promotes myogenesis from satellite cells to maintain skeletal muscle homeostasis.
Epidemiological characterization of a nosocomial outbreak of extended spectrum β‐lactamase Escherichia coli ST‐131 confirms the clinical value of core genome multilocus sequence typing
Authors: Woksepp Hanna , Ryberg Anna , Berglind Linda , Schön Thomas , Söderman Jan
Published: September 2017

Enhanced precision of epidemiological typing in clinically suspected nosocomial outbreaks is crucial. Our aim was to investigate whether single nucleotide polymorphism (SNP) analysis and core genome (cg) multilocus sequence typing (MLST) of whole genome sequencing (WGS) data would more reliably identify a nosocomial outbreak, compared to earlier molecular typing methods. Sixteen isolates from a nosocomial outbreak of ESBL E. coli ST‐131 in southeastern Sweden and three control strains were subjected to WGS. Sequences were explored by SNP analysis and cgMLST. cgMLST clearly differentiated between the outbreak isolates and the control isolates (>1400 differences). All clinically identified outbreak isolates showed close clustering (≥2 allele differences), except for two isolates (>50 allele differences). These data confirmed that the isolates with >50 differing genes did not belong to the nosocomial outbreak. The number of SNPs within the outbreak was ≤7, whereas the two discrepant isolates had >700 SNPs. Two of the ESBL E. coli ST‐131 isolates did not belong to the clinically identified outbreak. Our results illustrate the power of WGS in terms of resolution, which may avoid overestimation of patients belonging to outbreaks as judged from epidemiological data and previously employed molecular methods with lower discriminatory ability.
Impact of pain and remission in the functioning of patients with depression in Mainland China, Taiwan, and Hong Kong
Authors: Novick Diego , Shi Qiang , Yue Li , Moneta Maria Victoria , Siddi Sara , Haro Josep Maria
Published: September 2017

Introduction

The present study analyzes functioning during the course of treatment of a major depressive disorder in Mainland China, Taiwan, and Hong Kong.

Methods

Data in this post hoc analysis were taken from a 24‐week prospective, observational study in 12 countries worldwide. Of these, 422 patients were included from Mainland China (N = 205; 48.6%), Taiwan (N = 199; 47.2%), and Hong Kong (N = 18; 4.2%). Functioning was measured with the Sheehan Disability Scale, pain with the Somatic Symptom Inventory, and depression severity with the Quick Inventory of Depressive Symptomatology Self Report 16. Patients were classified as having no pain, persistent pain, or remitted pain. A mixed model with repeated measures was fitted to analyze the relationship between pain and functioning, adjusting for severity and other factors.

Results

At baseline, 40% of the patients had painful physical symptoms. At 24 weeks, 6% of the patients had persistent pain. Sixty percent of the patients achieved remission. Patients with pain had a higher severity of depression score and lower functioning (P < .05) at baseline. At 24 weeks, patients with persistent pain had lower functioning (P < .05). The regression model found that clinical remission was associated with higher functioning at endpoint and that patients with persistent pain had lower functioning at endpoint when compared with the no‐pain group.

Conclusions

Patients presenting with pain had lower functioning at baseline. At 24 weeks, pain persistence was associated with significantly lower functioning as measured by the Sheehan Disability Scale. Clinical remission was associated with better functional outcomes. The course of pain was related to achieving remission.
Survival after treatment with curative intent for hepatocellular carcinoma among patients with vs without non‐alcoholic fatty liver disease
Authors: Wong C. R. , Njei B. , Nguyen M. H. , Nguyen A. , Lim J. K.
Published: September 2017

Background

Non‐alcoholic fatty liver disease (NAFLD) is expected to become a leading aetiology of hepatocellular carcinoma (HCC)‐related mortality in the United States. HCC treatments with curative intent (OLT, orthotopic liver transplantation; resection; RFA, radiofrequency ablation) can improve survival in carefully selected patients.

Aim

To compare survival after receipt of curative treatment for NAFLD and non‐NAFLD‐HCC aetiologies (HCV, chronic hepatitis C; HBV, chronic hepatitis B; ALD, alcoholic liver disease) and by treatment was performed.

Methods

A cohort of 17 664 patients was assembled using linked Surveillance, Epidemiology, and End Results and Medicare data from 1991 to 2011 with confirmed diagnosis of HCC.

Results

The cohort was mostly male, aged 70 (21‐106) years, without cardiovascular disease, and had liver cirrhosis without decompensation, metastatic HCC or large tumour size (>5 cm). The NAFLD‐HCC group was mostly female and older with more cardiovascular disease, metastatic HCC, and large tumour size and less cirrhosis and decompensated liver disease than the non‐NAFLD‐HCC groups. The NAFLD group was 47% less likely to receive any curative treatment as compared with non‐NAFLD aetiologies (OR 0.53, P < .001). NAFLD‐HCC had worse median survival after OLT (3.2, 0‐12.9 years, P = .01) but had improved survival after resection (2.4, 0‐12.0 years, P < .001) as compared with non‐NAFLD‐HCC. No significant survival differences existed for RFA by HCC aetiology. NAFLD was not an independent predictor of mortality after OLT, resection or RFA.

Conclusion

Patients with NAFLD‐HCC had worse survival after OLT but favourable survival after resection, particularly in the absence of cirrhosis, as compared with non‐NAFLD‐HCC aetiologies.
Place and the spatial politics of intergenerational remembrance of the Iron Gates displacements in Romania, 1966–1972
Authors: Vãran Claudia , Creţan Remus
Published: September 2017

Post‐socialist memories recalling the communist past in Central and Eastern Europe have risen to importance in recent decades, but there is still a scarcity of literature dealing with the post‐socialist “post‐memory.” By adapting a social‐spatial narrative methodology to memory studies and by promoting the current theories on the spatial politics of (intergenerational) memory in general and more specifically on the post‐socialist memory formation, this paper aims to highlight the nature of memory, how intergenerational shaping of memory happens and the implications of these memories for understanding post‐socialist memory creation through an understanding of how people's personal connections (attachment) to place serve as the basis of intergenerational memory transmission. To set the scene, between 1966 and 1972, in alignment with the Stalinist principles of Soviet electrification, Romania and Yugoslavia completed the construction of one of the largest hydroelectric plants in Europe – the Iron Gates – on the Danube. Although the flooding of the settlements that were in the way of this project involved the destruction of property representing local cultural heritage, the dominant place‐based memories are those related to trauma and personal attachment to (materially gone) places. The shaping of memories for the post‐socialist generation is the foundation of people's difficulty in adapting to a market economy and the capitalist state. However, while the home becomes a locus for memory transmission between generations, post‐memories are “summarised” through certain key traumatic events. The implications of the creation of these memories are significant for understanding post‐socialist memory formation because post‐socialist remembrance of communism is bottom‐up, rooted in local events and grounded in place. Finally, in the context of claiming retroactive justice in contemporary Romanian politics, tensions between those manifesting counter‐memories (i.e., memories that challenge state‐led actions) and those with memories that reveal people's pride for the engineering achievements bring out the complex nature of these memories.
Effects of illite supplementation on in vitro and in vivo rumen fermentation, microbial population and methane emission of Hanwoo steers fed high concentrate diets
Authors: Biswas Ashraf A. , Lee Sung‐Sill , Mamuad Lovelia L. , Kim Seon‐Ho , Choi Yeon‐Jae , Lee Chanhee , Lee Kichoon , Bae Gui‐Seck , Lee Sang‐Suk
Published: September 2017

This study was conducted to evaluate the effects of feeding supplemental illite to Hanwoo steers on methane (CH4) emission and rumen fermentation parameters. An in vitro ruminal fermentation technique was conducted using a commercial concentrate as substrate and illite was added at different concentrations as treatments: 0%, 0.5%, 1.0%, and 2.0% illite. Total volatile fatty acids (VFA) were different (P < 0.05) at 24 h of incubation where the highest total VFA was observed at 1.0% of illite. Conversely, lowest CH4 production (P < 0.01) was found at 1.0% of illite. In the in vivo experiment, two diets were provided, without illite and with addition of 1% illite. An automated head chamber (GreenFeed) system was used to measure enteric CH4 production. Cattle received illite supplemented feed increased (P < 0.05) total VFA concentrations in the rumen compared with those fed control. Feeding illite numerically decreased CH4 production (g/day) and yield (g/kg dry matter intake). Rumen microbial population analysis indicated that the population of total bacteria, protozoa and methanogens were lower (P < 0.05) for illite compared with the control. Accordingly, overall results suggested that feeding a diet supplemented with 1% illite can have positive effects on feed fermentation in the rumen and enteric CH4 mitigation in beef cattle.
Estimation and Evaluation of Linear Individualized Treatment Rules to Guarantee Performance
Authors: Qiu Xin , Zeng Donglin , Wang Yuanjia
Published: September 2017

In clinical practice, an informative and practically useful treatment rule should be simple and transparent. However, because simple rules are likely to be far from optimal, effective methods to construct such rules must guarantee performance, in terms of yielding the best clinical outcome (highest reward) among the class of simple rules under consideration. Furthermore, it is important to evaluate the benefit of the derived rules on the whole sample and in pre-specified subgroups (e.g., vulnerable patients). To achieve both goals, we propose a robust machine learning method to estimate a linear treatment rule that is guaranteed to achieve optimal reward among the class of all linear rules. We then develop a diagnostic measure and inference procedure to evaluate the benefit of the obtained rule and compare it with the rules estimated by other methods. We provide theoretical justification for the proposed method and its inference procedure, and we demonstrate via simulations its superior performance when compared to existing methods. Lastly, we apply the method to the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial on major depressive disorder and show that the estimated optimal linear rule provides a large benefit for mildly depressed and severely depressed patients but manifests a lack-of-fit for moderately depressed patients.