bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overcoming constraints on the detection of recessive selection in human genes from population frequency data
Authors: Balick Daniel J. , Jordan Daniel M. , Sunyaev Shamil , Do Ron 
Published: May 2021

AbstractThe identification of genes that evolve under recessive natural selection is a longstanding goal of population genetics research with important applications to disease gene discovery. We found that commonly used methods to evaluate selective constraint at the gene level are highly sensitive to genes under heterozygous selection but ubiquitously fail to detect recessively evolving genes. Additionally, more sophisticated likelihood-based methods designed to detect recessivity similarly lack power for a human gene of realistic length from current population sample sizes. However, extensive simulations suggested that recessive genes may be detectable in aggregate. Here, we offer a method informed by population genetics simulations designed to detect recessive purifying selection in gene sets. Applying this to empirical gene sets produced significant enrichments for strong recessive selection in genes previously inferred to be under recessive selection in a consanguineous cohort and in genes involved in autosomal recessive monogenic disorders.
Learning dynamics by computational integration of single cell genomic and lineage information
Authors: Wang Shou-Wen , Klein Allon M. 
Published: May 2021

AbstractA goal of single cell genome-wide profiling is to reconstruct dynamic transitions during cell differentiation, disease onset, and drug response. Single cell assays have recently been integrated with lineage tracing, a set of methods that identify cells of common ancestry to establishbona fidedynamic relationships between cell states. These integrated methods have revealed unappreciated cell dynamics, but their analysis faces recurrent challenges arising from noisy, dispersed lineage data. Here, we develop coherent, sparse optimization (CoSpar) as a robust computational approach to infer cell dynamics from single-cell genomics integrated with lineage tracing. CoSpar is robust to severe down-sampling and dispersion of lineage data, which enables simpler, lower-cost experimental designs and requires less calibration. In datasets representing hematopoiesis, reprogramming, and directed differentiation, CoSpar identifies fate biases not previously detected, predicting transcription factors and receptors implicated in fate choice. Documentation and detailed examples for common experimental designs are available athttps://cospar.readthedocs.io/.
The non-genomic vitamin D pathway links β-amyloid to autophagic apoptosis in Alzheimer’s disease
Authors: Lai Rai-Hua , Hsu Yueh-Ying , Shie Feng-Shiun , Chen Mei-Hsin , Juang Jyh-Lyh 
Published: May 2021

AbstractVitamin D is an important hormonal molecule, which exerts genomic and non-genomic actions in maintaining brain development and adult brain health. Many epidemiological studies have associated vitamin D deficiency with Alzheimer’s disease (AD). Nevertheless, the underlying signaling pathway through which this occurs remains to be characterized. We were intrigued to find that although vitamin D levels are significantly low in AD patients, their hippocampal vitamin D receptor (VDR) levels are inversely increased in the cytosol of the brain cells, and colocalized with Aβ42 plaques, gliosis and autophagosomes, suggesting that a non-genomic form of VDR is implicated in AD. Mechanistically, Aβ42 induces the conversion of nuclear heterodimer of VDR/RXR heterodimer into a cytoplasmic VDR/p53 heterodimer. The cytosolic VDR/p53 complex mediates the Aβ42–induced autophagic apoptosis. Reduction of p53 activity in AD mice reverses the VDR/RXR formation and rescues AD brain pathologies and cognitive impairment. In line with the impaired genomic VDR pathway, the transgenic AD mice fed a vitamin D sufficient diet exhibit lower plasma vitamin D levels since early disease phases, raising the possibility that vitamin D deficiency may actually be an early manifestation of AD. Despite the deficiency of vitamin D in AD mice, vitamin D supplementation not only has no benefit but lead to exacerbated Aβ42 depositions and cognitive impairment. Together, these data indicate that the impaired genomic vitamin D pathway links Aβ42 to induce autophagic apoptosis, and suggest that VDR/p53 pathway could be targeted for the treatment of AD.Significance StatementVitamin D exerts a genomic action for neuroprotection through VDR/RXR transcriptional complex. Thus, insufficient vitamin D has been linked to AD, but the signaling pathway involved remains unclear. Surprisingly, we find that the genomic action of VDR/RXR to be compromised and converted into a non-genomic VDR/p53 complex in promoting AD neurodegeneration. The cytosolic VDR/p53 complex contribute to autophagy-induced neuronal apoptosis. The VDR/RXR pathway can be a new therapeutic target for AD because targeting VDR/p53 ameliorates AD. Importantly, we provide evidence that vitamin D deficiency might be an early AD manifestation, and vitamin D supplementation exacerbates AD. This work uncovers a non-genomic VDR action in promoting AD and suggests a potential aggravating effect of vitamin D supplementation on AD.
Generation of dynamic three-dimensional genome structure through phase separation of chromatin
Authors: Fujishiro Shin , Sasai Masaki 
Published: May 2021

AbstractThree-dimensional genome structure and dynamics play critical roles in regulating DNA functions. Flexible chromatin structure and movements suggested that the genome is dynamically phase-separated to form A (active) and B (inactive) compartments in interphase nuclei. Here, we examined this hypothesis by developing a polymer model of the whole genome of human cells and assessing the impact of phase separation on genome structure. Upon entry to the G1 phase, the simulated genome expanded according to heterogeneous repulsion among chromatin chains, which moved chromatin heterogeneously, inducing phase separation of chromatin. This repulsion-driven phase separation quantitatively reproduces the experimentally observed chromatin domains, A/B compartments, lamina-associated domains, and nucleolus-associated domains, consistently explaining nuclei of different human cells and predicting their dynamic fluctuations. We propose that phase separation induced by heterogeneous repulsive interactions among chromatin chains largely determines dynamic genome organization.SignificanceDNA functions in living cells are crucially affected by the three-dimensional genome structure and dynamics. We analyzed the whole genome of human cells by developing a polymer model of interphase nuclei. The model revealed the essential importance of the unfolding process of chromosomes from the condensed mitotic state for describing the interphase nuclei; through the unfolding process, heterogeneous repulsive interactions among chromatin chains induced phase separation of chromatin, which quantitatively explains the experimentally observed various genomic data. We can use this model structure as a platform to analyze the relationship among genome structure, dynamics, and functions.
Genomic surveillance of vancomycin-resistantEnterococcus faeciumreveals spread of a linear plasmid conferring a nutrient utilization advantage
Authors: Boumasmoud Mathilde , Haunreiter Vanina Dengler , Schweizer Tiziano A. , Meyer Lilly , Chakrakodi Bhavya , Schreiber Peter W. , Seidl Kati , Kühnert Denise , Kouyos Roger D. , Zinkernagel Annelies S. 
Published: May 2021

AbstractHealthcare-associated outbreaks of vancomycin-resistantEnterococcus faecium(VREfm) are a worldwide problem with increasing prevalence. The genomic plasticity of this hospital-adapted pathogen contributes to its efficient spread despite infection control measures. Here, we aimed to identify the genomic and phenotypic determinants of healthcare-associated transmission of VREfm. We assessed the VREfm transmission networks at the tertiary-care University Hospital of Zurich (USZ) between October 2014 and February 2018 and investigated microevolutionary dynamics of this pathogen. We performed whole-genome sequencing for the 69 VREfm isolates collected during this timeframe and assessed the population structure and variability of the vancomycin resistance transposon. Phylogenomic analysis allowed us to reconstruct transmission networks and to unveil external or indirect transmission networks, not detectable by traditional surveillance. Notably, it unveiled a persistent clone, sampled 31 times over a 29-month period. Exploring the evolutionary dynamics of this clone and characterizing the phenotypic consequences revealed the spread of a variant with decreased daptomycin susceptibility and the acquired ability to utilize N-acetyl-galactosamine (GalNAc), one of the primary constituents of the human gut mucins. This nutrient utilization advantage was conferred by a novel plasmid, termed pELF_USZ, which exhibited a linear topology. This plasmid, which was harbored by two distinct clones, was transferable by conjugation. Overall, this work provides an example of the potential of the integration of epidemiological, functional genomic and evolutionary perspectives to understand adaptation strategies contributing to the successful spread of VREfm.Significance statementSequencing microbial pathogens causing outbreaks has become a common practice to characterize transmission networks. In addition to the signal provided by vertical evolution, bacterial genomes harbor mobile genetic elements, shared horizontally between clones. While macroevolutionary studies have revealed an important role of plasmids and genes encoding carbohydrate utilization systems in the adaptation ofEnterococcus faeciumto the hospital environment, mechanisms of dissemination and the specific function of many of these genetic determinants remain to be elucidated. Here, we characterize a plasmid providing a nutrient utilization advantage and show evidence for its clonal and horizontal spread at a local scale. Further studies integrating epidemiological, functional genomics and evolutionary perspectives will be critical to identify changes shaping the success of this pathogen.
Crop loss identification at field parcel scale using satellite remote sensing and machine learning
Authors: Hiremath Santosh , Wittke Samantha , Palosuo Taru , Kaivosoja Jere , Tao Fulu , Proll Maximilian , Puttonen Eetu , Peltonen-Sainio Pirjo , Marttinen Pekka , Mamitsuka Hiroshi 
Published: May 2021

AbstractIdentifying crop loss at field parcel scale using satellite images is challenging: first, crop loss is caused by many factors during the growing season; second, reliable reference data about crop loss are lacking; third, there are many ways to define crop loss. This study investigates the feasibility of using satellite images to train machine learning (ML) models to classify agricultural field parcels into those with and without crop loss. The reference data for this study was provided by Finnish Food Authority (FFA) containing crop loss information of approximately 1.4 million field parcels in Finland covering about 3.5 million ha from 2000 to 2015. This reference data was combined with Normalised Difference Vegetation Index (NDVI) derived from Landsat 7 images, in which more than 80% of the possible data are missing. Despite the hard problem with extremely noisy data, among the four ML models we tested, random forest (with mean imputation and missing value indicators) achieved the average AUC (area under the ROC curve) of 0.688±0.059 over all 16 years with the range [0.602, 0.795] in identifying new crop-loss fields based on reference fields of the same year. To our knowledge, this is one of the first large scale benchmark study of using machine learning for crop loss classification at field parcel scale. The classification setting and trained models have numerous potential applications, for example, allowing government agencies or insurance companies to verify crop-loss claims by farmers and realise efficient agricultural monitoring.
Agrin/Lrp4 signal constrains MuSK activity during neuromuscular synapse development in appendicular muscle
Authors: Walker Lauren J , Roque Rebecca A , Navarro Maria F , Granato Michael 
Published: May 2021

ABSTRACTThe receptor tyrosine kinase MuSK, its co-receptor Lrp4 and the Agrin ligand constitute a signaling pathway critical in axial muscle for neuromuscular synapse development, yet whether this pathway functions similarly in appendicular muscle is unclear. Here, using the larval zebrafish pectoral fin, equivalent to tetrapod forelimbs, we show that like axial muscle, developing appendicular muscles develop aneural acetylcholine receptor (AChR) clusters prior to innervation. As motor axons arrive, neural AChR clusters form, eventually leading to functional synapses in a MuSK-dependent manner. Surprisingly, we find that loss of Agrin or Lrp4 function, which abolishes synaptic AChR clusters in axial muscle, results in enlarged presynaptic nerve endings and progressively expanding appendicular AChR clusters, mimicking the consequences of motoneuron ablation. Moreover,muskdepletion inlrp4mutants partially restores synaptic AChR patterning. Combined, our results provide compelling evidence that, in contrast to axial muscle in which Agrin/Lrp4 stimulates MuSK activity, Agrin/Lrp4 signaling in appendicular muscle constrains MuSK activity to organize neuromuscular synapses. Thus, we reveal a previously unappreciated role for Agrin/Lrp4 signaling, thereby highlighting distinct differences between axial and appendicular synapse development.
Improved methods for protein and single-molecule RNA detection inC. elegansembryos
Authors: Parker Dylan M. , Winkenbach Lindsay P. , Parker Annemarie , Boyson Sam , Nishimura Erin Osborne 
Published: May 2021

ABSTRACTVisualization of gene products inCaenorhabditis eleganshas provided insights into the molecular and biological functions of many novel genes in their native contexts. Single-molecule FluorescenceIn SituHybridization (smFISH) and Immunofluorescence (IF) visualize the abundance and localization of mRNAs and proteins, respectively, allowing researchers to elucidate the localization, dynamics, and functions of many genes. Here, we describe several improvements and optimizations to existing IF and smFISH approaches specifically for use inC. elegansembryos. We present 1) optimized fixation and permeabilization steps to preserve cellular morphology while maintaining probe and antibody accessibility, 2) a streamlined, in-tube approach that negates freeze-cracking, 3) the smiFISH (single molecule inexpensive FISH) adaptation that reduces cost, 4) an assessment of optimal anti-fade products, and 5) straightforward quantification and data analysis methods. Most importantly, published IF and smFISH protocols have predominantly been mutually exclusive, preventing exploration of relationships between an mRNA and a relevant protein in the same sample. Here, we present methods to combine IF and smFISH protocols inC. elegansembryos including an efficient method harnessing nanobodies. Finally, we discuss tricks and tips to help the reader optimize and troubleshoot individual steps in each protocol.
Corrosion of a chrome-moly pipe transporting sulfuric acid in a demineralization section: a failure analysis
Authors: Marquez Andres , Maharaj Chris 
Published: May 2021

PurposeThe purpose of this study was to carry out an analysis of the corrosion failure on a chrome-moly pipeline transporting highly concentrated sulfuric acid in a demineralization section at a petrochemical plant, along with the feasibility of using inhibitors to minimize the corrosive effects of sulfuric acid.Design/methodology/approachX-ray fluorescence spectroscopy, high-resolution optical microscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy and accelerated corrosion experiments (ACE) were performed.FindingsErosion-corrosion failure was confirmed by the significant reduction in thickness of the internal surface of the material exposed to sulfuric acid, as well as the formation of an oxide scale/layer. ACE accurately predicted high material loss from exposure to sulfuric acid. Moreover, adding ascorbic acid as a corrosion inhibitor (even at low concentrations) was found to reduce the oxidation by more than 50% in the presence of sulfuric acid.Originality/valueThe main idea/purpose of this work relies on the analysis of recurrent real-life corrosion-attributed failures that are common in industry but are not properly addressed for a variety of reasons, poor management and lack of corrosion preventive strategies being the main ones. This study once again highlights readily available solutions/implementations that are capable of not only addressing technically the issue investigated but also, and as important, economically. By using microscopic imaging, reliable well-tested and widely used characterization methods, all combined with basic experiments and tests, the nature of the repetitive failure investigated was clearly demonstrated as well as readily available alternatives to minimize it in the short term. Nevertheless, implementing material selection techniques appropriately as effective corrosion prevention/control and cost-saving strategies must be enforced in any process.
An assessment of the determinants of licensing of university patents: a survey of Spanish universities
Authors: Miranda F. Javier , Pérez-Mayo Jesús , García-Gallego José Manuel , Valero-Amaro Víctor , Rubio Sergio 
Published: May 2021

PurposeThis work tries to shed light on what factors can influence, positively or negatively, the decision to license a patent from a university, in order to offer some recommendations that can contribute to increasing the number of patents licensed from universities.Design/methodology/approachBased on a sample of researchers at Spanish universities who have already registered patents, this work shows that the individual factors of the researcher outweigh the institutional factors in determining the decision to patent an invention. Likewise, the probability of patenting an invention is higher when the researcher's level of participation in the process is greater.FindingsThe results of our study allow us to affirm that, in the Spanish university setting, individual factors play a more important role in one's decision to license a patent than institutional factors. In this sense, the collaboration of companies or experts from outside of academia in the research from which the patent was granted is the most relevant factor.Originality/valueThis work, the first study of this type to be carried out in Europe, concludes with a recommendation for reinforcing the structure and functionality of technology transfer offices as a basic policy for the promotion and facilitation of commercial exploitation of innovation in the universities.
Webcare as a signal: exhaustive-selective webcare strategy and brand evaluation
Authors: Jeesha Krishnan , Purani Keyoor 
Published: May 2021

Purpose
Keeping in mind the growing significance of online reviews, management of responses to the customer reviews – webcare – is becoming important in recent times. How a firm responds to online reviews can send a signal to the readers of the reviews contributing to their brand evaluations. From a strategic perspective, a firm should decide if they should respond to all reviews or respond to only a select few reviews. This study aims to provide an understanding of how exhaustive and selective webcare influence brand evaluations. It also explores the role of review balance and review frame, which potentially act as moderators, on such influences.

Design/methodology/approach
Three scenario-based experiments were used to manipulate the webcare strategy (exhaustive-selective) and the potential moderators (review balance and review frame). The 910 participants of the single-stage experiments were identified using an online panel managed by UK-based Prolific Academic.

Findings
Exhaustive webcare is found to be the most effective strategy for influencing brand evaluations in all conditions. Also, two interesting results were found, which can have practical implications. A selective negative strategy is as effective as an exhaustive webcare in almost all cases, and a selective positive webcare is as good as not having a webcare in nearly all cases. Changes in webcare effectiveness due to the influence of review balance and review frame were established.

Research limitations/implications
With the review reader perspective and focus on brand management, this study may trigger enquiries into effects of webcare strategies on brand evaluations and other outcomes such as word-of-mouth. The interaction effects of the various strategies adopted together on brand evaluation and loyalty have not been explored and would be of interest to academicians and managers.

Practical implications
Firms need to plan a careful resource deployment while responding to the online consumer reviews as responding to a select few reviews may yield the same effects as that of exhaustive webcare. Brand managers may find responding only to positive reviews futile, as it could be as good as having no webcare. Also, the strategy of responding to reviews needs to be adapted based on the online review platform where the set in which the review is read is different.

Originality/value
This is one of the few studies focusing on the effects of webcare on brand evaluations from a review reader perspective as against the dominant reviewer perspective. This research also presents hitherto unexplored effects of an exhaustive-selective webcare strategy on brand evaluations.
Entropy generation of a nanofluid in a porous cavity with sinusoidal temperature at the walls and a heat source bellow
Authors: Cimpean Dalia Sabina , Pop Ioan 
Published: May 2021

Purpose
This paper aims to focus on the analysis of the entropy generation in an inclined square cavity filled with a porous media saturated by a nanofluid with sinusoidal temperature distribution on the side walls, adiabatic conditions on the upper wall and a heat source at the lower wall.

Design/methodology/approach
The two-phase nanofluid model including the Brownian diffusion and thermophoresis effects has been used for simulation of nanofluid transport inside the porous cavity. The governing equations and the entropy generation owing to fluid friction, heat and mass transfer are transformed in terms of the dimensionless variables, and the results are obtained by using the finite difference method of the second-order accuracy.

Findings
The numerical results of the model are investigated, and the effect of different important parameters, such as inclination angle of the cavity, amplitude ratio of the sinusoidal temperature or phase deviation, is discussed. The results for no inclination of the cavity is compared and successfully validated with previous reported results of the literature. The important findings of the study are focused mainly on the existence of the irreversibility phenomena which are affected by the conditions of the model and the values of the studied parameters.

Originality/value
The originality of this work is given by the presented mathematical model, the numerical solution with new results for entropy generation in an inclined porous cavity filled by a nanofluid and the applications for design of electronic or energy devices.