bluuebunny/crossref_metadata_2025 huggingface dataset:
Pluronic gel-based burrowing assay for rapid assessment of neuromuscular health inC. elegans
Authors: Lesanpezeshki Leila , Hewitt Jennifer E. , Laranjeiro Ricardo , Antebi Adam , Driscoll Monica , Szewczyk Nathaniel J. , Blawzdziewicz Jerzy , Lacerda Carla M.R. , Vanapalli Siva A.
Published: May 2019

Whole-organism phenotypic assays are central to the assessment of neuromuscular function and health in model organisms such as the nematodeC. elegans. In this study, we report a new assay format for engagingC. elegansin burrowing that enables rapid assessment of nematode neuromuscular health. In contrast to agar environments that pose specific drawbacks for characterization ofC. elegansburrowing ability, here we use the optically transparent and biocompatible Pluronic F-127 gel that transitions from liquid to gel at room temperature, enabling convenient and safe handling of animals. The burrowing assay methodology involves loading animals at the bottom of well plates, casting a liquid-phase of Pluronic on top that solidifies via a modest temperature upshift, enticing animals to reach the surface via chemotaxis to food, and quantifying the relative success animals have in reaching the chemoattractant. We study the influence of Pluronic concentration, gel height and chemoattractant choice to optimize assay performance. To demonstrate the simplicity of the assay workflow and versatility, we show its novel application in multiple areas including (i) evaluating muscle mutants with defects in dense bodies and/or M-lines (pfn-3, atn-1, uig-1, dyc-1, zyx-1, unc-95andtln-1), (ii) tuning assay conditions to reveal changes in the mutantgei- 8, (iii) sorting of fast burrowers in a genetically-uniform wild-type population for later quantitation of their distinct muscle gene expression, and (iv) testing proteotoxic animal models of Huntington and Parkinson’s disease. Results from our studies show that stimulating animals to navigate in a dense environment that offers mechanical resistance to three- dimensional locomotion challenges the neuromuscular system in a manner distinct from standard crawling and thrashing assays. Our simple and high throughput burrowing assay can provide insight into molecular mechanisms for maintenance of neuromuscular health and facilitate screening for therapeutic targets.
HYPERsol: flash-frozen results from archival FFPE tissue for clinical proteomics
Authors: Marchione Dylan M. , Ilieva Ilyana , Garcia Benjamin A. , Pappin Darryl J. , Wilson John P. , Wojcik John B.
Published: May 2019

Massive formalin-fixed, paraffin-embedded (FFPE) tissue archives exist worldwide, representing a potential gold mine for clinical proteomics research. However, current protocols for FFPE proteomics lack standardization, efficiency, reproducibility, and scalability. Here we present High-Yield Protein Extraction and Recovery by direct SOLubilization (HYPERsol), an optimized workflow using adaptive-focused acoustics (AFA) ultrasonication and S-Trap sample processing that enables proteome coverage and quantification from FFPE samples comparable to that achieved from flash-frozen tissue (average R = 0.936).
Molecular competition in G1 controls when cells simultaneously commit to terminally differentiate and exit the cell-cycle
Authors: Zhao Michael L. , Rabiee Atefeh , Kovary Kyle M. , Bahrami-Nejad Zahra , Taylor Brooks , Teruel Mary N.
Published: May 2019

Terminal differentiation is essential for the development and maintenance of tissues in all multi-cellular organisms and is associated with a permanent exit from the cell cycle. Failure to permanently exit the cell cycle can result in cancer and disease. However, the molecular mechanisms and timing that coordinates differentiation commitment and cell cycle exit are not yet understood. Here using adipogenesis as a model system to track differentiation commitment in live cells, we show that a rapid switch mechanism engages exclusively in G1 to trigger a simultaneous commitment to differentiate and permanently exit from the cell cycle. We identify a signal integration mechanism whereby the strengths of both mitogen and differentiation stimuli control a molecular competition between cyclin D1 and PPARG-induced expression of the CDK inhibitor p21 which in turn regulates if and when the differentiation switch is triggered and when the proliferative window closes. In this way, the differentiation control system is able to couple mitogen and differentiation stimuli to sustain a long-term balance between terminally differentiating cells and maintaining the progenitor cell pool, a parameter of critical importance for enabling proper development of tissue domains and organs.

HIGHLIGHTS

Progenitor cells both commit to terminally differentiate and permanently exit the cell cycle at a precise time in G1 as a result of a competition process that can last over multiple cell cycles.

Positive-feedback driven expression of PPARG and the parallel induction of p21 triggers a rapid commitment to terminally differentiate and then maintains a postmitotic adipocyte state.

Opposing mitogen and adipogenic signals are funneled into a molecular competition in G1 phase that controls if and when cells commit to differentiate, which in turn regulates the number of differentiated cells produced while allowing for the maintenance of sufficient progenitor cells.
Population genetic simulation study of power in association testing across genetic architectures and study designs
Authors: Ming Hay Tong Dominic , Hernandez Ryan D.
Published: May 2019

While it is well established that genetics can be a major contributor to population variation of complex traits, the relative contributions of rare and common variants to phenotypic variation remains a matter of considerable debate. Here, we simulate rare variant association studies across different case/control panel sampling strategies, sequencing methods, and genetic architecture models based on evolutionary forces to determine the statistical performance of RVATs widely in use. We find that the highest statistical power of RVATs is achieved by sampling case/control individuals from the extremes of an underlying quantitative trait distribution. We also demonstrate that the use of genotyping arrays, in conjunction with imputation from a whole genome sequenced (WGS) reference panel, recovers the vast majority (90%) of the power that could be achieved by sequencing the case/control panel using current tools. Finally, we show that for dichotomous traits, the statistical performance of RVATs decreases as rare variants become more important in the trait architecture. Our results extend previous work to show that RVATs are insufficiently powered to make generalizable conclusions about the role of rare variants in dichotomous complex traits.
Sphingolipid production by gut Bacteroidetes regulates glucose homeostasis
Authors: Johnson Elizabeth L. , Heaver Stacey L. , Waters Jillian L. , Kim Benjamin I. , Bretin Alexis , Goodman Andrew L. , Gewirtz Andrew T. , Worgall Tilla S. , Ley Ruth E.
Published: May 2019

Levels of Bacteroidetes in the gut microbiome are positively associated with insulin resistance (IR) in humans. Considering that IR is promoted by elevations in hepatic sphingolipids (SL), particularly ceramides, and that Bacteroidetes are the only microbiome phylum possessing genes encoding serine palmitoyltransferase (SPT), which mediates SL synthesis, we investigated a potential link between bacterial SL production, host SL metabolism, and IR.In vitro, bacterial SLs entered colonocytes and were metabolized into complex SL, including ceramides. In mice, administration of WTBacteroides thetaiotaomicron, but not a SPT-deficient mutant, resulted in elevated levels of liver ceramides and reduced responsiveness to exogenously administered insulin. This work establishes bacterial SLs as a new class of microbiome-derived molecule capable of impacting host metabolism.

One Sentence Summary

SL production by gut Bacteroidetes regulates liver ceramide levels and insulin sensitivity.
Biogeographic patterns of ectomycorrhizal fungal communities associated withCastanopsis sieboldiiacross the Japanese archipelago
Authors: Matsuoka Shunsuke , Iwasaki Takaya , Sugiyama Yoriko , Kawaguchi Eri , Doi Hideyuki , Osono Takashi
Published: May 2019

Biogeographic patterns in ectomycorrhizal (ECM) fungal communities and their drivers have been elucidated, including effects of host tree species and abiotic (climatic and edaphic) conditions. At these geographic scales, genotypic diversity and composition of single host tree species change with spatial and environmental gradients, reflecting their historical dispersal events. However, whether the host genotypes can be associated with the biogeographic patterns of ECM communities remains unclear. We investigated the biogeographic pattern of ECM fungal community associated with the single host speciesCastanopsis sieboldii(Fagaceae), whose genotypic diversity and composition across the Japanese archipelago has already been evaluated, and we quantified the effect of host genotypes on the biogeographic pattern. Richness and community composition of ECM fungi changed with latitude and longitude; these biogeographic changes of ECM community were significantly explained by host genotypic variables. Quantitative analyses showed a higher relative explanatory power of climatic and spatial variables than that of host genotypic variables for the biogeographic patterns in the ECM community. Our results suggest the importance of historical events of host dispersal in determining the biogeographic patterns of the ECM fungal community, while their explanation power was lower than that for climatic filtering and/or fungal dispersal.
Analysis of soybean germination, emergence, and prediction of a possible northward expansion of the crop under climate change
Authors: Lamichhane Jay Ram , Constantin Julie , Schoving Céline , Maury Pierre , Debaeke Philippe , Aubertot Jean-Noël , Dürr Carolyne
Published: May 2019

Soybean (Glycine max (L.) Merr.) has potential to improve sustainability of agricultural production systems. A higher focus on this crop is needed to re-launch its production in the EU. A better understanding of key determinants affecting soybean establishment represents a first step to facilitate its adoption in cropping systems. To this objective, we conducted laboratory and field experiments in order to better characterize seed germination and seedling growth in relation to temperatures, water content, and soil structure. We then used these data to parametrize the SIMPLE crop emergence model and to evaluate its prediction quality, by comparing observed field germination and emergence data with the predicted ones. Finally, we performed a simulation study over the 2020-2100 period, for three sowing dates, from mid-March to mid-April, in the northern climate of France to evaluate whether future climate change will help expand soybean from Southern to Northern part of the country. Soybean germination was very fast, taking only 15 °C days to reach 50% germination at optimal conditions. The base, optimum and maximum temperatures were determined as 4, 30 and 40°C, respectively while the base water potential was −0.7 MPa, indicating a high sensitivity to water stress. The SIMPLE model well-predicted germination and emergence courses and their final rates, compared with the observed field data. The simulation study showed average emergence rate ranging from 61 to 78% with little variability among sowing dates and periods, but a high variability between years. Main causes of non-emergence were seedling mortality due to clods or soil surface crust followed by non-germination and seedling mortality due to drought, especially for mid-April sowing. These results provide a better knowledge of soybean establishment that are encouraging to introduce soybean with early sowings to diversify current cropping systems.
Cornelia-de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect
Authors: Olley Gabrielle , Pradeepa Madapura M. , FitzPatrick David R. , Bickmore Wendy A. , Boumendil Charlene
Published: May 2019

Cornelia de Lange Syndrome is a multisystem developmental disorder typically caused by mutations in the gene encoding the cohesin loader NIPBL. The associated phenotype is generally assumed to be the consequence of aberrant transcriptional regulation. Recently, we identified a residue substitution in BRD4 associated with a Cornelia de Lange-like syndrome, that reduces BRD4 binding to acetylated histones. Here we show that, although this mutation reduces BRD4-occupancy at enhancers in mouse embryonic stem cells, it does not affect transcription. Rather it delays the cell cycle, increases DNA damage signalling, and perturbs regulation of DNA repair in mutant cells. This uncovers a new role for BRD4 in DNA repair pathway choice. Furthermore, we find evidence of a similar increase in DNA damage signalling in cells derived from NIPBL-deficient individuals, suggesting that defective DNA damage signalling and repair is also a feature of typical Cornelia de Lange Syndrome.
Sustained perturbation in functional connectivity induced by cold pain
Authors: Makovac Elena , Dipasquale Ottavia , Jackson Jade B , Medina Sonia , O’Daly Owen , O’Muircheartaigh Jonathan , de Lara Rubio Alfonso , Williams Steven CR , McMahon Stephen B , Howard Matthew A
Published: May 2019

Functional connectivity (FC) perturbations have been reported in multiple chronic pain phenotypes, but the nature of reported changes is varied and inconsistent between cohorts. Increases and decreases in connectivity strength in task negative and positive networks, for example, the default mode and salience networks (DMN/SN), respectively, have been described, but how other networks are effected, for example, descending pain control networks, remains unknown. Whether connectivity changes relate to peripherally-mediated nociceptive afferent input, represent coping strategies or are sequelae of chronic pain, e.g. anxiety/depression, is also unknown. Here, we examined FC changes in response to experimentally-administered tonic cold pain in healthy volunteers as a means of disambiguating the nature of connectivity changes. We assessed FC prior to, during, and following tonic cold painful stimulation in four seed regions: ventromedial prefrontal cortex (vmPFC), rostral anterior insula (rAI), subgenual anterior cingulate cortex (ACC) and periaqueductal grey (PAG) and recorded subjectively reported pain using a computerised visual analogue scale. We saw DMN FC changes during painful stimulation and that inter-network communication between the rAI and sgACC seeds with the vmPFC became less anti-correlated during pain, whereas PAG-precuneus FC decreased. Pain-induced FC alterations largely persisted during a 6-minute recovery period following cessation of the painful stimulus. Observed FC changes related to the magnitude of individuals’ subjectively reported pain. We provide new insights into FC changes during and following tonic cold-pain and suggest that some FC changes observed in chronic pain patients may relate to the presence of an ongoing afferent peripheral drive.
Deep serum proteomics reveal biomarkers and causal candidates for type 2 diabetes
Authors: Gudmundsdottir Valborg , Emilsson Valur , Aspelund Thor , Ilkov Marjan , Gudmundsson Elias F , Zilhão Nuno R , Lamb John R , Jennings Lori L , Gudnason Vilmundur
Published: May 2019

The prevalence of type 2 diabetes mellitus (T2DM) is expected to increase rapidly in the next decades, posing a major challenge to societies worldwide. The emerging era of precision medicine calls for the discovery of biomarkers of clinical value for prediction of disease onset, where causal biomarkers can furthermore provide actionable targets. Blood-based factors like serum proteins are in contact with every organ in the body to mediate global homeostasis and may thus directly regulate complex processes such as aging and the development of common chronic diseases. We applied a data-driven proteomics approach measuring serum levels of 4,137 proteins in 5,438 Icelanders to discover novel biomarkers for incident T2DM and describe the serum protein profile of prevalent T2DM. We identified 536 proteins associated with incident or prevalent T2DM. Through LASSO penalized logistic regression analysis combined with bootstrap resampling, a panel of 20 protein biomarkers that accurately predicted incident T2DM was identified with a significant incremental improvement over traditional risk factors. Finally, a Mendelian randomization analysis provided support for a causal role of 48 proteins in the development of T2DM, which could be of particular interest as novel therapeutic targets.
Microbial communities profiling in intensive care units expose limitations in current sanitary standards
Authors: Ribeiro Lucas Ferreira , Lopes Erica M. , Kishi Luciano T. , Ribeiro Liliane Fraga Costa , Menegueti Mayra Gonçalves , Gaspar Gilberto Gambero , Silva-Rocha Rafael , Guazzaroni María Eugenia
Published: May 2019

Hospital-associated infections (HAIs) are the leading cause of morbidity and mortality in intensive care units (ICUs) and neonatal intensive care units (NICUs). Organisms causing these infections are often present on surfaces around the patient. Given that microbiotas may vary across different ICUs, the HAI-related microbial signatures within these units remain underexplored. In this study, we use deep-sequencing analyses to explore and compare the structure of bacterial communities at inanimate surfaces of the ICU and NICU wards of The Medical School Clinics Hospital (Brazil). The data revealed that NICU presents higher biodiversity than ICU and surfaces closest to the patient showed a peculiar microbiota, distinguishing one unit from the other. Several facultative anaerobes or obligate anaerobes HAI-related genera were classified as biomarkers for the NICU, whereasPseudomonaswas the main biomarker for ICU. Correlation analyses revealed a distinct pattern of microbe-microbe interactions for each unit, including bacteria able to form multi-genera biofilms. Furthermore, we evaluated the effect of concurrent cleaning over the ICU bacterial community. The results showed that, although some bacterial populations decreased after cleaning, various HAI-related genera were quite stable to sanitization, suggesting being well-adapted to the ICU environment. Overall, these results enabled identification of discrete ICU and NICU reservoirs of potentially pathogenic bacteria and provided evidence for the presence of a set of biomarkers that distinguish these units. Moreover, the study exposed the inconsistencies of the routine cleaning to minimize HAI-related genera contamination.

IMPORTANCE

Due to the high impact of HAIs, there is an urgent need for the development of robust policies on microbial surveillance to help guide procedures, improving infection control. To the best of our knowledge, this is the first comprehensive study, using a high-throughput approach, focused on comparing the microbiota peculiarities of the ICU and NICU in one of the largest public hospitals in Brazil. The work highlighted bacteria associated with nosocomial infections, identifying the most potent reservoirs of contamination, and evaluated the microbiota changes related to the cleaning procedure. Therefore, this study contributes to increase the knowledge about (N)ICUs microbiomes and may help to reduce health-care-associated infections, especially in developing countries.
A global screen for assembly state changes of the mitotic proteome by SEC-SWATH-MS
Authors: Heusel Moritz , Frank Max , Köhler Mario , Amon Sabine , Frommelt Fabian , Rosenberger George , Bludau Isabell , Aulakh Simran , Linder Monika I. , Liu Yansheng , Collins Ben C. , Gstaiger Matthias , Kutay Ulrike , Aebersold Ruedi
Published: May 2019

Living systems integrate biochemical reactions that determine the functional state of each cell. Reactions are primarily mediated by proteins that have in systematic studies been treated as independent entities, disregarding their higher level organization into complexes which affects their activity and/or function and is thus of great interest for biological research. Here, we describe the implementation of an integrated technique to quantify cell state-specific changes in the physical arrangement of protein complexes, concurrently for thousands of proteins and hundreds of complexes. Applying this technique for comparison of human cells in interphase and mitosis, we provide a systematic overview of mitotic proteome reorganization. The results recall key hallmarks of mitotic complex remodeling and discover new events, such as a new model of nuclear pore complex disassembly, validated by orthogonal methods. To support the interpretation of quantitative SEC-SWATH-MS datasets, we extend the software CCprofiler and provide an interactive exploration tool, SECexplorer-cc.

Highlights

Quantification of proteome assembly state changes using SEC-SWATH-MS

Systems-wide analysis of assembly state changes in the mitotic proteome

Discovery and validation of a novel mitotic disassembly intermediate of the nuclear pore complex

Higher sensitivity and information content compared to thermostability-based approaches for global measurement of proteome states

SECexplorer, an online platform to browse results and investigate proteins newly implicated in cell division
Genomics of sorghum local adaptation to a parasitic plant
Authors: Bellis Emily S. , Kelly Elizabeth A. , Lorts Claire M. , Gao Huirong , DeLeo Victoria L. , Rouhan Germinal , Budden Andrew , Bhaskara Govinal Badiger , Hu Zhenbin , Muscarella Robert , Timko Michael P. , Nebie Baloua , Runo Steven M. , Chilcoat N. Doane , Juenger Thomas E. , Morris Geoffrey P. , dePamphilis Claude W. , Lasky Jesse R.
Published: May 2019

Host-parasite coevolution can maintain high levels of genetic diversity in traits involved in species interactions. In many systems, host traits exploited by parasites are constrained by use in other functions, leading to complex selective pressures across space and time. Here, we study genome-wide variation in the staple crop Sorghum bicolor (L.) Moench and its association with the parasitic weed Striga hermonthica (Delile) Benth., a major constraint to food security in Africa. We hypothesize that geographic selection mosaics across gradients of parasite occurrence maintain genetic diversity in sorghum landrace resistance. Suggesting a role in local adaptation to parasite pressure, multiple independent loss-of-function alleles at sorghum LOW GERMINATION STIMULANT 1 (LGS1) are broadly distributed among African landraces and geographically associated with S. hermonthica occurrence. However, low frequency of these alleles within S. hermonthica-prone regions and their absence elsewhere implicate potential tradeoffs restricting their fixation. LGS1 is thought to cause resistance by changing stereochemistry of strigolactones, hormones that control plant architecture and belowground signaling to mycorrhizae and are required to stimulate parasite germination. Consistent with tradeoffs, we find signatures of balancing selection surrounding LGS1 and other candidates from analysis of genome-wide associations with parasite distribution. Experiments with CRISPR-Cas9 edited sorghum further indicate the benefit of LGS1-mediated resistance strongly depends on parasite genotype and abiotic environment and comes at the cost of reduced photosystem gene expression. Our study demonstrates long-term maintenance of diversity in host resistance genes across smallholder agroecosystems, providing a valuable comparison to both industrial farming systems and natural communities.

SIGNIFICANCE STATEMENT

Understanding co-evolution in crop-parasite systems is critical to management of myriad pests and pathogens confronting modern agriculture. In contrast to wild plant communities, parasites in agricultural ecosystems are usually expected to gain the upper hand in co-evolutionary ‘arms races’ due to limited genetic diversity of host crops in cultivation. Here, we develop a framework to characterize associations between genome variants in global landraces (traditional varieties) of the staple crop sorghum with the distribution of the devastating parasitic weed Striga hermonthica. We find long-term maintenance of diversity in genes related to parasite resistance, highlighting an important role of host adaptation for co-evolutionary dynamics in smallholder agroecosystems.
AP-1 Imprints a Reversible Transcriptional Program of Senescent Cells
Authors: Martínez-Zamudio Ricardo Iván , Roux Pierre-François , de Freitas José Américo N L F , Robinson Lucas , Doré Gregory , Sun Bin , Gil Jesús , Herbig Utz , Bischof Oliver
Published: May 2019

Senescent cells play important physiological- and pathophysiological roles in tumor suppression, tissue regeneration, and aging. While select genetic and epigenetic elements crucial for senescence induction were identified, the dynamics, underlying epigenetic mechanisms, and regulatory networks defining senescence competence, induction and maintenance remain poorly understood, precluding a deliberate therapeutic manipulation of these dynamic processes. Here, we show, using dynamic analyses of transcriptome and epigenome profiles, that the epigenetic state of enhancers predetermines their sequential activation during senescence. We demonstrate that activator protein 1 (AP-1) ‘imprints’ the senescence enhancer landscape effectively regulating transcriptional activities pertinent to the timely execution of the senescence program. We define and validate a hierarchical transcription factor (TF) network model and demonstrate its effectiveness for the design of senescence reprogramming experiments. Together, our findings define the dynamic nature and organizational principles of gene-regulatory elements driving the senescence program and reveal promising inroads for therapeutic manipulation of senescent cells.
Development of Kinetic Modeling to Assess Multi-functional Vascular Response to Low Dose Radiation in Leukemia
Authors: Brooks Jamison , Kumar Bijender , Zuro Darren M. , Raybuck Jonathon D. , Madabushi Srideshikan Sargur , Vishwasrao Paresh , Parra Liliana Echavarria , Kortylewski Marcin , Armstrong Brian , Hui Susanta K
Published: May 2019

Vascular permeability, tissue transfer rate (Ktrans), fractional extracellular tissue space (νec) and blood perfusion are crucial parameters to assess bone marrow vasculature (BMV) function. However, quantitative measurements of these parameters in a mouse model are difficult because of limited resolution of standard macroscopic imaging modalities. Using intravital multiphoton microscopy (MPM), live imaging of dextran transfer from BMV to calvarium tissue of mice bearing acute lymphoblastic leukemia (ALL) was performed to obtain BMV parameters. Mice bearing ALL had increased BMV permeability, altered Ktrans, increased νec, decreased blood perfusion, and increased BMV permeability resulting in reduced drug uptake. Targeted 2 Gy radiation therapy (RT) to mice bearing ALL increased local BMV perfusion and ALL chemotherapy uptake (P<0.0001 and P=0.0036, respectively), suggesting RT prior to chemotherapy treatment may increase treatment efficacy. Developed MPM techniques allow for a quantitative assessment of BMV functional parameters not previously performed with microscopic or macroscopic imaging.
Method for Modeling Residual Variance in Biomedical Signals Applied to Transcranial Doppler Ultrasonography Waveforms
Authors: Jalaleddini Kian , Thorpe Samuel G. , Canac Nicolas , Dorn Amber Y. , Thibeault Corey M. , Wilk Seth J. , Hamilton Robert B.
Published: May 2019

Transcranial Doppler (TCD) ultrasonography measures pulsatile cerebral blood flow velocity in the arteries and veins of the head and neck. The velocity pulse waveform morphology has been shown to have physiological and diagnostic significance. However, the measured pulses may exhibit a high degree of variability that deteriorates the estimates of clinical parameters. This study characterizes the TCD residual variance that result in pulse variability.

We retrospectively utilized the data from 82 subjects. A trained sonographer insonated the middle cerebral arteries using a 2MHz hand-held probe. We implemented a multi-stage algorithm to identify the TCD residuals in each scan: pulses were identified; outlier pulses were flagged and removed; the average pulse waveform was taken as the ensemble average of the accepted pulse waveforms; finally, the resampled average pulse waveforms subtracted from individual pulses were taken as the TCD residuals. For each scan, we reported the signal to noise ratio and parameterized models for residuals: their amplitude structure using probability density function models and their temporal structure using autoregressive models.

The signal to noise ratio 90% range was [1.7, 18.2] dB. The estimated probability density functions were best characterized by a generalized normal distribution whose beta parameter was smaller than 2 in 93% of scans. The identified frequency structure showed the dynamics were low-pass in nature.

Analysis of the TCD residuals is useful in the assessment of the signal quality. Moreover, our identified models can also be used to generate synthetic TCD signal that enables future realistic simulation studies.
Cholesterol deprivation induces TGFβ signaling to promote basal differentiation in pancreatic cancer
Authors: Cornell Linara G. , Peri Suraj , Restifo Diana , Klochkova Alena , Hartman Tiffiney R. , O’Reilly Alana M. , Francescone Ralph , Franco-Barraza Janusz , Shah Neelima , Nicolas Emmanuelle , Handorf Elizabeth A. , Cai Kathy Q. , Mazitova Alexandra , Sloma Ido , Chiaverelli Rachel , Moffitt Richard , Golemis Erica A. , Cukierman Edna , Astsaturov Igor
Published: May 2019

Oncogenic transformation alters the metabolism of cellular nutrients to sustain tumor growth. We here define a mechanism by which modifications in cholesterol metabolism control the formation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by means of conditional inactivation ofNsdhlin mice bearing a tumor-inducingKrasmutation (KrasG12D) prevented PDAC formation in the context of a heterozygousTrp53f/+genotype without impairing normal pancreatic development. In mice with pancreaticNsdhlablation and homozygous loss ofTrp53, the emerging tumors presented with the aggressive basal (mesenchymal) phenotype as opposed to the classic (glandular) PDAC. This paralleled significantly reduced expression of cholesterol metabolic pathway genes in human basal PDAC subtype. Mechanistically, we demonstrate that genetic or metabolic cholesterol deprivation stabilizes the transforming growth factor beta (TGFβ) receptor to activate pro-mesenchymal effectors in human and murine PDAC, providing a direct mechanism by which cholesterol metabolism can condition tumor differentiation.
PilT and PilU are homohexameric ATPases that coordinate to retract type IVa pili
Authors: Chlebek Jennifer L. , Hughes Hannah Q. , Ratkiewicz Aleksandra S. , Rayyan Rasman , Wang Joseph Che-Yen , Herrin Brittany E. , Dalia Triana N. , Biais Nicolas , Dalia Ankur B.
Published: May 2019

Bacterial type IV pili are critical for diverse biological processes including horizontal gene transfer, surface sensing, biofilm formation, adherence, motility, and virulence. These dynamic appendages extend and retract from the cell surface. In many type IVa pilus systems, extension occurs through the action of an extension ATPase, often called PilB, while optimal retraction requires the action of a retraction ATPase, PilT. Many type IVa systems also encode a homolog of PilT called PilU. However, the function of this protein has remained unclear becausepilUmutants exhibit inconsistent phenotypes among type IV pilus systems and because it is relatively understudied compared to PilT. Here, we study the type IVa competence pilus ofVibrio choleraeas a model system to define the role of PilU. We show that the ATPase activity of PilU is critical for pilus retraction in PilT Walker A and/or Walker B mutants. PilU does not, however, contribute to pilus retraction in ΔpilTstrains. Thus, these data suggest that PilU is abona fideretraction ATPase that supports pilus retraction in a PilT-dependent manner. We also found that a ΔpilUmutant exhibited a reduction in the force of retraction suggesting that PilU is important for generating maximal retraction forces. Additionalin vitroandin vivodata show that PilT and PilU act as independent homo-hexamers that may form a complex to facilitate pilus retraction. Finally, we demonstrate that the role of PilU as a PilT-dependent retraction ATPase is conserved inAcinetobacter baylyi, suggesting that the role of PilU described here may be broadly applicable to other type IVa pilus systems.

Author Summary

Almost all bacterial species use thin surface appendages called pili to interact with their environments. These structures are critical for the virulence of many pathogens and represent one major way that bacteria share DNA with one another, which contributes to the spread of antibiotic resistance. To carry out their function, pili dynamically extend and retract from the bacterial surface. Here, we show that retraction of pili in some systems is determined by the combined activity of two motor ATPase proteins.
Impact of functional synapse clusters on neuronal response selectivity
Authors: Ujfalussy Balázs B , Makara Judit K
Published: May 2019

Clustering of functionally similar synapses in dendrites is thought to affect input-output transformation by inducing dendritic nonlinearities. However, neither the in vivo impact of synaptic clusters on somatic membrane potential (sVm), nor the rules of cluster formation are elucidated. We developed a computational approach to measure the effect of functional synaptic clusters on sVm response of biophysical model CA1 and L2/3 pyramidal neurons to behaviorally relevant in vivo-like inputs. Large-scale dendritic spatial inhomogeneities in synaptic tuning properties did influence sVm, but small synaptic clusters appearing randomly with unstructured connectivity did not. With structured connectivity, ~10-20 synapses per cluster was optimal for clustering-based tuning, but larger responses were achieved by 2-fold potentiation of the same synapses. We further show that without nonlinear amplification of the effect of random clusters, action potential-based, global plasticity rules can not generate functional clustering. Our results suggest that clusters likely form via local synaptic interactions, and have to be moderately large to impact sVm responses.
Monitoring the depth of anesthesia using Autoregressive model and Sample entropy
Authors: Zhu Fu G. , Luo Xiao G. , Hou Chang J. , Huo Dan Q. , Dang Peng
Published: May 2019

Anesthesia is an important part in modern surgery, and the way how to effectively monitor the depth of anesthesia (DOA) is core issue in the anesthesia work. Since anesthetics mainly affected the brain of patients, it is very effective to monitor DOA by electroencephalogram (EEG). This paper proposes a method for monitoring DOA using EEG. First, the sample entropy (SampEn) of EEG were calculated as a feature vector. Simultaneously, the Burg recursive algorithm was used to solve the autoregressive model (AR model) and AR coefficients were extracted as feature vectors. Later, according to the characteristics of uneven distribution of sample points, the weighted k-nearest neighbor (WKNN) classifier was selected. The Anesthesia was divided into awake, mild, moderate and deep by WKNN classifier. According to the results, the correlation coefficient between the SampEn of the EEG and Bispectral Index (BIS) is above 0.8. There is a correlation between the first five orders of AR coefficient and the BIS index, and the correlation of the second order reaches 0.8. Through the validation of 30 patients, this method can assessment of DOA effectively and accurately.
Structure ofAspergillus aculeatusβ-1,4-galactanase in complex with galactobiose
Authors: Torpenholt Søs , Poulsen Jens-Christian N. , Muderspach Sebastian Jannick , De Maria Leonardo , Lo Leggio Leila
Published: May 2019

β-1,4-Galactanases are glycoside hydrolases that are involved in the degradation of pectin and belong to family 53 in the classification of glycoside hydrolases. Previous studies have elucidated the structures of several fungal and two bacterial galactanases, while biochemical studies have indicated differences in the product profiles of different members of the family. Structural studies of ligand complexes have to date been limited to the bacterial members of the family. Here, the first structure of a fungal galactanase in complex with a disaccharide is presented. Galactobiose binds to subsites −1 and −2, thus improving our understanding of ligand binding to galactanases.
Structures of soluble rabbit neprilysin complexed with phosphoramidon or thiorphan
Authors: Labiuk Shaunivan L. , Sygusch Jurgen , Grochulski Pawel
Published: May 2019

Neutral endopeptidase (neprilysin; NEP) is a proteinase that cleaves a wide variety of peptides and has been implicated in Alzheimer's disease, cardiovascular conditions, arthritis and other inflammatory diseases. The structure of the soluble extracellular domain (residues 55–750) of rabbit neprilysin was solved both in its native form at 2.1 Å resolution, and bound to the inhibitors phosphoramidon and thiorphan at 2.8 and 3.0 Å resolution, respectively. Consistent with the extracellular domain of human neprilysin, the structure reveals a large central cavity which contains the active site and the location for inhibitor binding.
Crystal structure and Hirshfeld surface analysis of (E)-2-(2,4,6-trimethylbenzylidene)-3,4-dihydronaphthalen-1(2H)-one
Authors: Baydere Cemile , Taşçı Merve , Dege Necmi , Arslan Mustafa , Atalay Yusuf , Golenya Irina A.
Published: May 2019

A novel chalcone, C20H20O, derived from benzylidenetetralone, was synthesized via Claissen–Schmidt condensation between tetralone and 2,4,6-trimethylbenzaldehyde. In the crystal, molecules are linked by C—H...O hydrogen bonds, producing R
2
2(20) and R
2
4(12) ring motifs. In addition, weak C—H...π and π-stacking interactions are observed. The intermolecular interactions were investigated using Hirshfeld surface analysis and two-dimensional fingerprint plots, revealing that the most important contributions for the crystal packing are from H...H (66.0%), H...C/ C...H (22.3%), H...O/O...H (9.3%), and C...C (2.4%) interactions. Shape-index plots show π–π stacking interactions and the curvedness plots show flat surface patches characteristic of planar stacking.
N-[2-(Trifluoromethyl)phenyl]maleamic acid: crystal structure and Hirshfeld surface analysis
Authors: Suchetan P. A. , Prakash Shet M. , Lokanath N. K. , Naveen S. , Warad Ismail
Published: May 2019

The title molecule, C11H8F3NO3, adopts a cis configuration across the –C=C– double bond in the side chain and the dihedral angle between the phenyl ring and side chain is 47.35 (1)°. The –COOH group adopts a syn conformation (O=C—O—H = 0°), unlike the anti conformation observed in related maleamic acids. In the crystal, inversion dimers linked by pairs of O—H...O hydrogen bonds are connected via N—H...O hydrogen bonds and C—H...O interactions into (100) sheets, which are cross-linked by another C—H...O interaction to result in a three-dimensional network. The Hirshfeld surface fingerprint plots show that the highest contribution to surface contacts arises from O...H/H...O contacts (26.5%) followed by H...F/F...H (23.4%) and H...H (17.3%).
Managing online product assortment and order fulfillment for superior e-tailing service experience
Authors: Kautish Pradeep , Sharma Rajesh
Published: May 2019

Purpose

The purpose of this paper is to bridge together seemingly disparate yet interconnected paradigmatic antecedents of e-tailing and servicescape, i.e., product assortment, order fulfillment, shopping assistance and its consequences for shopping efficiency.

Design/methodology/approach

The proposed conceptual model is well grounded in the extensive literature from e-tailing as well as retailing domain and to assess the plausibility of the model. Total 246 female online apparel shoppers were surveyed from an Indian university and the data were analyzed using structural equation modeling through SmartPLS.

Findings

The outcomes of the study indicate that the e-customer may derive a substantial share of shopping assistance and service interface through product assortment offered by e-tailing sites. Customer-perceived performance of this e-shopping process – a crucial element of e-tail servicescape – directly affects the shopping assistance, along with order fulfillment capability of retail scope.

Research limitations/implications

The study used a sample of graduate students at a north-west university in India, which limits the generalizability of the research to other consumer groups. The paper links a significant body of literature within a conceptually developed framework and identifies key research areas in the e-tailing realm.

Practical implications

By better understanding the role of product assortment as a value-added feature in online value co-creation process, the e-tail managers can leverage the proposed integrated capability to improve e-tailing performance and customer outcomes in the form of business.

Social implications

With rapid advancements in internet-led communication, we are witnessing the dawn of a new era of e-tail innovations around us which is expected to change the way people experience shopping.

Originality/value

This research is an attempt to enrich the level of understanding about online shopping environment in light of relationships among virtual and physical facets of e-tail, i.e., product assortment, order fulfillment, shopping assistance and shopping efficiency. The authors investigate customer-perceived product assortment performance in e-tailing and its significances on shopping outcomes.
Online stakeholder dialogue:quo vadis? – An empirical analysis in German-speaking countries
Authors: Hetze Katharina , Bögel Paula Maria , Emde Andreas , Bekmeier-Feuerhahn Sigrid , Glock Yvonne
Published: May 2019

Purpose

The purpose of this paper is to present an empirical analysis of CSR communication posted on the websites of 70 companies listed on the main stock markets in German-speaking countries, the so-called DACH region. The results of this analysis offer answers to questions that are currently being discussed in the CSR literature, namely, on the importance attributed to stakeholder information vs stakeholder dialogues in (online) CSR communication.

Design/methodology/approach

Using a quantitative content analysis, the study examines the extent to which leading German, Austrian and Swiss companies are meeting communication and CSR-related requirements, especially regarding stakeholder dialogue and overall stakeholder involvement.

Findings

Drawing on Morsing and Schultz’s (2006) theoretical insights concerning stakeholder engagement, this study shows that current CSR communication primarily provides information for stakeholders and contains only a few elements of consultation with stakeholders. In addition, no elements indicating stakeholder involvement in decision processes were found. Data analysed in 2004, 2007, 2012 and 2016 for the German DAX companies allowed for comparisons over time. A closer examination of these data revealed increasing professionalism in CSR communication, especially in the provision and presentation of information. Regarding information clarity and opportunities for dialogue, however, the results show low progress. The criteria set developed for the study provides guidance for how companies can improve their CSR communication, but the findings on the long-term slow progress in stakeholder involvement, in some aspects even a decrease in dialogue, also raise questions about the (perceived) use of online CSR dialogues for companies.

Research limitations/implications

Communication is viewed from a strategic instrumental perspective. The empirical analysis focusses on the technical possibilities offered by the internet to make CSR communications and reporting available and understandable to stakeholders and to promote dialogue with and among stakeholders.

Originality/value

By focussing on online CSR communication in the DACH region, this study contributes to the current state of research and offers several recommendations for practitioners; it particularly provides critical reflection on online stakeholder dialogues and related paradigms (constitutive vs functionalistic perspective).
Modelling and simulation of the expansion of a shape memory polymer stent
Authors: Liu Ruoxuan , Mcginty Sean , Cui Fangsen , Luo Xiaoyu , Liu Zishun
Published: May 2019

Purpose

The purpose of this paper is to demonstrate the feasibility of using shape memory polymer (SMP) for developing vascular stent. In particular, the expansion performance is analyzed through extensive modeling and simulation.

Design/methodology/approach

Firstly, the authors construct the model geometry and propose a constitutive model to describe the deformation of the stent due to the expansion process. The authors then simulate the expansion process under varying conditions, including different heating rates and recovery temperatures. Finally, the authors analyze the radial strength of the SMP stent.

Findings

A less invasive and stable expansion performance of the SMP stent is confirmed by the simulation method. A fitting function of the expansion process is proposed based on the characteristics of the SMP.

Research limitations/implications

The effects of dynamic blood flow on the SMP stent is ignored. A fluid-structure interaction analysis may need to be considered to give a more accurate description of the behaviour of the SMP stent.

Practical implications

The findings will provide guidance for the rational design and application of SMP stents.

Social implications

The work will provide guidance for the new generation stent design.

Originality/value

This is the first time that the expansion performance of a SMP stent has been analyzed both qualitatively and quantitatively through modelling and simulation.
Stabilised MLS in MLPG method for heat conduction problem
Authors: Singh Rituraj , Singh Krishna Mohan
Published: May 2019

Purpose

The purpose of this paper is to assess the performance of the stabilised moving least squares (MLS) scheme in the meshless local Petrov–Galerkin (MLPG) method for heat conduction method.

Design/methodology/approach

In the current work, the authors extend the stabilised MLS approach to the MLPG method for heat conduction problem. Its performance has been compared with the MLPG method based on the standard MLS and local coordinate MLS. The patch tests of MLS and modified MLS schemes have been presented along with the one- and two-dimensional examples for MLPG method of the heat conduction problem.

Findings

In the stabilised MLS, the condition number of moment matrix is independent of the nodal spacing and it is nearly constant in the global domain for all grid sizes. The shifted polynomials based MLS and stabilised MLS approaches are more robust than the standard MLS scheme in the MLPG method analysis of heat conduction problems.

Originality/value

The MLPG method based on the stabilised MLS scheme.