bluuebunny/crossref_metadata_2025 huggingface dataset:
TheEnterprise: A massive transposon carryingSpokmeiotic drive genes
Authors: Vogan Aaron A. , Ament-Velásquez S. Lorena , Bastiaans Eric , Wallerman Ola , Saupe Sven J. , Suh Alexander , Johannesson Hanna
Published: March 2020

The genomes of eukaryotes are full of parasitic sequences known as transposable elements (TEs). Most TEs studied to date are relatively small (50 – 12000 bp), but can contribute to very large proportions of genomes. Here we report the discovery of a giant tyrosine-recombinase-mobilized DNA transposon,Enterprise, from the model fungusPodospora anserina. Previously, we described a large genomic feature called theSpokblock which is notable due to the presence of meiotic drive genes of theSpokgene family. TheSpokblock ranges from 110 kb to 247 kb and can be present in at least four different genomic locations withinP. anserina, despite what is an otherwise highly conserved genome structure. We have determined that the reason for its varying positions is that theSpokblock is not only capable of meiotic drive, but is also capable of transposition. More precisely, theSpokblock represents a unique case where theEnterprisehas captured theSpoks, thereby parasitizing a resident genomic parasite to become a genomic hyperparasite. Furthermore, we demonstrate thatEnterprise(without theSpoks) is found in other fungal lineages, where it can be as large as 70 kb. Lastly, we provide experimental evidence that theSpokblock is deleterious, with detrimental effects on spore production in strains which carry it. In contrast to the selfish role of theEnterpriseinP. anserina, we hypothesize that the mobility of theEnterprisemay also play an adaptive role in fungi whenEnterpriseundergoes horizontal transfer while carrying metabolic genes. This union of meiotic drivers and a transposon has created a selfish element of impressive size inPodospora, challenging our perception of how TEs influence genome evolution and broadening the horizons in terms of what the upper limit of transposition may be.
In vitroandIn vivoGenetic Disease Modelling via NHEJ-precise deletions using CRISPR/Cas9
Authors: López-Manzaneda Sergio , Ojeda-Pérez Isabel , Zabaleta Nerea , Garcia-Torralba Aída , Alberquilla Omaira , Torres Raúl , Sanchez-Dominguez Rebeca , Torella Laura , Olivier Emmanuel , Mountford Joanne , Ramírez Juan C. , Bueren Juan A. , González-Aseguinolaza Gloria , Segovia Jose-Carlos
Published: March 2020

Development of advanced gene and cell therapies for the treatment of genetic diseases requires confident animal and cellular models to test their efficacy and is crucial in the cases where no primary samples from patients are available. CRISPR/Cas9 technology, has become one of the most spread endonuclease tools for editing the genome at will. Moreover, it is known that the use of two guides tends to produce the precise deletion between the guides via NHEJ. Different distances between guides were tested (from 8 to 500 base pairs). We found that distances between the two cutting sites and orientation of Cas9 protein-DNA interaction are important for the efficiency within the optimal range (30-60 bp), we could obtain new genetically reproducible models for two rare disease, a Pyruvate Kinase Deficiency model, using human primary cells, and a (forin vivoprimary hyperoxaluria therapeutic mouse model. We demonstrate that the use of a 2-guideRNAs at the optimal distance and orientation is a powerful strategy for disease modelling in those diseases where the availability of primary cells is limited.
The bacterial community structure dynamics inMeloidogyne incognitainfected roots and its role in worm-microbiome interactions
Authors: Yergaliyev Timur , Alexander-Shani Rivka , Dimeretz Hanna , Pivonia Shimon , Bird David McK. , Rachmilevitch Shimon , Szitenberg Amir
Published: March 2020

Background

Plant parasitic nematodes such asMeloidogyne incognitahave a complex life cycle, occurring sequentially in various niches of the root and rhizosphere. They are known to form a range of interactions with bacteria and other microorganisms, that can affect their densities and virulence. High throughput sequencing can reveal these interactions in high temporal, and geographic resolutions, although thus far we have only scratched the surface. We have carried out a longitudinal sampling scheme, repeatedly collecting rhizosphere soil, roots, galls and second stage juveniles from 20 plants to provide a high resolution view of bacterial succession in these niches, using 16S rRNA metabarcoding.

Results

We find that a structured community develops in the root, in which gall communities diverge from root segments lacking a gall, and that this structure is maintained throughout the crop season. We detail the successional process leading toward this structure, which is driven by interactions with the nematode and later by an increase in bacteria often found in hypoxic and anaerobic environments. We show evidence that this structure may play a role in the nematode’s chemotaxis towards uninfected root segments. Finally, we describe the J2 epibiotic microenvironment as ecologically deterministic, in part, due to active bacterial attraction of second stage juveniles.

Conclusions

High density sampling, both temporally and across adjacent microniches, coupled with the power and relative low cost of metabarcoding, has provided us with a high resolution description of our study system. Such an approach can advance our understanding of holobiont ecology.Meloidogynespp., with their relatively low genetic diversity, large geographic range and the simplified agricultural ecosystems they occupy, can serve as a model organism. Additionally, the perspective this approach provides could promote the efforts toward biological control efficacy.
Revisiting animal photo-identification using deep metric learning and network analysis
Authors: Miele Vincent , Dussert Gaspard , Spataro Bruno , Chamaillé-Jammes Simon , Allainé Dominique , Bonenfant Christophe
Published: March 2020

An increasing number of ecological monitoring programs rely on photographic capture-recapture of individuals to study distribution, demography and abundance of species. Photo-identification of individuals can sometimes be done using idiosyncratic coat or skin patterns, instead of using tags or loggers. However, when performed manually, the task of going through photographs is tedious and rapidly becomes too time consuming as the number of pictures grows.

Computer vision techniques are an appealing and unavoidable help to tackle this apparently simple task in the big-data era. In this context, we propose to revisit animal re-identification using image similarity networks and metric learning with convolutional neural networks (CNNs), taking the giraffe as a working example.

We first developed an end-to-end pipeline to retrieve a comprehensive set of re-identified giraffes from about 4, 000 raw photographs. To do so, we combined CNN-based object detection, SIFT pattern matching, and image similarity networks. We then quantified the performance of deep metric learning to retrieve the identity of known individuals and detect unknown individuals never seen in the previous years of monitoring.

After a data augmentation procedure, the re-identification performance of the CNN reached a Top-1 accuracy of about 90%, despite the very small number of images per individual in the training data set. While the complete pipeline succeeded in re-identifying known individuals, it slightly under-performed with unknown individuals.

Fully based on open-source software packages, our work paves the way for further attempts to build automatic pipelines for re-identification of individual animals, not only in giraffes but also in other species.
Inhibition of mTOR signaling by genetic removal of p70 S6 Kinase 1 leads to anxiety-like disorders
Authors: Koehl Muriel , Ladeveze Elodie , Catania Caterina , Cota Daniela , Abrous Djoher Nora
Published: March 2020

The mechanistic target or rapamycin (mTOR) is a ubiquitously expressed kinase that acts through two complexes, mTORC1 and mTORC2, to regulate protein homeostasis as well as long lasting forms of synaptic and behavioral plasticity. Alteration of the mTOR pathway is classically involved in neurodegenerative disorders, and it has been linked to dysregulation of cognitive functions and affective states. However, information concerning the specific involvement of the p70 S6 kinase 1 (S6K1), a downstream target of the mTORC1 pathway, in learning and memory processes and in the regulation of affective states remains scant. To fill this gap, we exposed adult male mice lacking S6K1 to a battery of behavioral tests aimed at measuring their learning and memory capabilities by evaluating reference memory and flexibility with the Morris water maze, and associative memory using the contextual fear conditioning task. We also studied their anxiety- and depression-like behaviors by respectively performing elevated plus maze, open field, light-dark emergence tests, and sucrose preference and forced swim tests. We found that deleting S6K1 leads to a robust anxious phenotype concomitant with associative learning deficits; these symptoms are associated with a reduction of adult neurogenesis and neuronal atrophy in the hippocampus. Collectively, these results provide grounds for the understanding of anxiety reports after treatments with mTOR inhibitors and will be critical for the development of novel compounds targeting anxiety.
EASE: EM-Assisted Source Extraction from calcium imaging data
Authors: Zhou Pengcheng , Reimer Jacob , Zhou Ding , Pasarkar Amol , Kinsella Ian , Froudarakis Emmanouil , Yatsenko Dimitri V , Fahey Paul G , Bodor Agnes , Buchanan JoAnn , Bumbarger Dan , Mahalingam Gayathri , Torres Russel , Dorkenwald Sven , Ih Dodam , Lee Kisuk , Lu Ran , Macrina Thomas , Wu Jingpeng , da Costa Nuno , Reid R. Clay , Tolias Andreas S , Paninski Liam
Published: March 2020

Combining two-photon calcium imaging (2PCI) and electron microscopy (EM) provides arguably the most powerful current approach for connecting function to structure in neural circuits. Recent years have seen dramatic advances in obtaining and processing CI and EM data separately. In addition, several joint CI-EM datasets (with CI performed in vivo, followed by EM reconstruction of the same volume) have been collected. However, no automated analysis tools yet exist that can match each signal extracted from the CI data to a cell segment extracted from EM; previous efforts have been largely manual and focused on analyzing calcium activity in cell bodies, neglecting potentially rich functional information from axons and dendrites. There are two major roadblocks to solving this matching problem: first, dense EM reconstruction extracts orders of magnitude more segments than are visible in the corresponding CI field of view, and second, due to optical constraints and non-uniform brightness of the calcium indicator in each cell, direct matching of EM and CI spatial components is nontrivial.

In this work we develop a pipeline for fusing CI and densely-reconstructed EM data. We model the observed CI data using a constrained nonnegative matrix factorization (CNMF) framework, in which segments extracted from the EM reconstruction serve to initialize and constrain the spatial components of the matrix factorization. We develop an efficient iterative procedure for solving the resulting combined matching and matrix factorization problem and apply this procedure to joint CI-EM data from mouse visual cortex. The method recovers hundreds of dendritic components from the CI data, visible across multiple functional scans at different depths, matched with densely-reconstructed three-dimensional neural segments recovered from the EM volume. We publicly release the output of this analysis as a new gold standard dataset that can be used to score algorithms for demixing signals from 2PCI data. Finally, we show that this database can be exploited to (1) learn a mapping from 3d EM segmentations to predict the corresponding 2d spatial components estimated from CI data, and (2) train a neural network to denoise these estimated spatial components. This neural network denoiser is a stand-alone module that can be dropped in to enhance any existing 2PCI analysis pipeline.
In vivo analysis of the evolutionary conserved BTD-box domain of Sp1 and Btd during Drosophila development
Authors: Blom-Dahl David , Córdoba Sergio , Gabilondo Hugo , Carr-Baena Pablo , Díaz-Benjumea Fernando J. , Estella Carlos
Published: March 2020

The Sp family of transcription factors plays important functions during development and disease. An evolutionary conserved role for some Sp family members is the control of limb development. The family is characterized by the presence of three C2H2-type zinc fingers and an adjacent 10 aa region with an unknown function called the Buttonhead (BTD) box. The presence of this BTD-box in all Sp family members identified from arthropods to vertebrates, suggests that it plays an important role during development. However, despite its conservation, thein vivofunction of the BTD-box has never been studied. In this work, we have generated specific BTD-box deletion alleles for theDrosophilaSp family membersSp1andbuttonhead(btd) using gene editing tools and analyzed its role during development. Unexpectedly,btdandSp1mutant alleles that lack the BTD-box are viable and have almost normal appendages. However, in a sensitized background the requirement of this domain to fully regulate some of Sp1 and Btd target genes is revealed. Furthermore, we have also identified a novel Sp1 role promoting legvsantenna identity through the repression ofspineless(ss) expression in the leg, a function that also depends on the Sp1 BTD-box.
Insights into the Polyhexamethylene Biguanide (PHMB) Mechanism of Action on Bacterial Membrane and DNA: A Molecular Dynamics Study
Authors: Sowlati-Hashjin Shahin , Carbone Paola , Karttunen Mikko
Published: March 2020

Polyhexamethylene biguanide (PHMB) is a cationic polymer with antimicrobial and antiviral properties. It has been commonly accepted that the antimicrobial activity is due the ability of PHMB to perforate the bacterial phospholipid membrane leading ultimately to its death. In this study we show by the means of atomistic molecular dynamics (MD) simulations that while the PHMB molecules attach to the surface of the phospholipid bilayer and partially penetrate it, they do not cause any pore formation at least within the microsecond simulation times. The polymers initially adsorb onto the membrane surface via the favourable electrostatic interactions between the phospholipid headgroups and the biguanide groups, and then partially penetrate the membrane slightly disrupting its structure. This, however, does not lead to the formation of any pores. The microsecond-scale simulations reveal that it is unlikely for PHMB to spontaneously pass through the phospholipid membrane. Our findings suggest that PHMB translocation across the bilayer may take place through binding to the phospholipids. Once inside the cell, the polymer can effectively ‘bind’ to DNA through extensive interactions with DNA phosphate backbone, which can potentially block the DNA replication process or activate DNA repair pathways.

TOC Graphic
Conformational states of the cytoprotective protein Bcl-xL
Authors: Ryzhov P. , Tian Y. , Yao Y. , Bobkov A. A. , Im W. , Marassi F. M.
Published: March 2020

Bcl-xL is a major inhibitor of apoptosis, a fundamental homeostatic process of programmed cell death that is highly conserved across evolution. Because it plays prominent roles in cancer, Bcl-xL is a major target for anti-cancer therapy and for studies aimed at understanding its structure and activity. While Bcl-xL is active primarily at intracellular membranes, most studies have focused on soluble forms of the protein lacking both the membrane-anchoring C-terminal tail and the intrinsically disordered loop, and this has resulted in a fragmented view of the protein’s biological activity. Here we describe how these segments affect the protein’s conformation and ligand binding activity in both its soluble and membrane-anchored states. The combined data from nuclear magnetic resonance (NMR) spectroscopy, molecular dynamics (MD) simulations, and isothermal titration calorimetry (ITC) provide information about the molecular basis for the protein’s functionality and a view of its complex molecular mechanisms.

SIGNIFICANCE

The human protein Bcl-xL is a key regulator of programmed cell death in health and disease. Structural studies, important for understating the molecular basis for its functions, have advanced primarily by deleting both the long disordered loop that regulates its activity and the C-terminal tail that anchors the protein to intracellular membranes Here we describe the preparation and conformations of full-length Bcl-xL in both its water-soluble and membrane-anchored states. The study provides new biophysical insights about Bcl-xL and its greater Bcl-2 protein family.
Poisson poisoning as the mechanism of action of the microtubule-targeting agent colchicine
Authors: Hemmat M. , Braman M. , Escalante D. , Odde D.J.
Published: March 2020

Microtubule-directed anti-cancer drugs, such as paclitaxel, vinblastine, and colchicine, disrupt cell mitosis through suppression of microtubule dynamics (“kinetic stabilization”). However, while the molecular mechanisms of paclitaxel and vinblastine act as pseudo- and true-kinetic stabilizers, respectively, the molecular mechanism of colchicine has remained enigmatic since it requires explanation of both the slow kinetics of the drug and suppression of microtubule dynamics. In this work, we applied an integrated multi-scale modeling-experimental approach to systematically characterize the microtubule targeting agent (MTA) colchicine. We found that colchicine stabilizes microtubule dynamics significantly bothin vivoandin vitroin a time and concentration-dependent manner. Molecular modeling results suggest that tubulin’s binding pocket is accessible to the drug for only 15% of the simulation trajectory time in straight and 82% in curved conformation on average, confirming that colchicine mainly binds to free tubulin. Molecular dynamics simulations show that there are conformational changes at longitudinal and lateral residues of GTP-tubulin-colchicine compared to a lattice tubulin structure, explaining why further incorporation of tubulin dimers to a tubulin-colchicine complex at a protofilament tip is unfavorable. Thermokinetic modeling of microtubule assembly shows that colchicine bound at fractions as low as ∼0.008 to free tubulin can poison the ends of protofilaments with a Poisson distribution and thus, reduce the microtubule growth rate, while stabilizing the tubulin lateral bond and reducing the microtubule shortening rate, i.e. true kinetic stabilization. This study suggests new strategies for colchicine administration to improve the therapeutic window in the treatment of cancer and inflammatory diseases.

Significance Statement

Colchicine is an ancient microtubule targeting agent (MTA) known to attenuate microtubule (MT) dynamics but its cancer treatment efficacy is often limited by lack of a detailed understanding of the drug’s mechanism of action. The primary goal of this study was to perform a multi-scale systematic analysis of molecular mechanism of action of colchicine. The analysis indicates that unlike paclitaxel and vinblastine, colchicine poisons the ends of protofilaments of MTs at low fractions bound to tubulin, in a time-dependent manner. Our results suggest new insights into improvement of the clinical administration of colchicine and new colchicine-site inhibitors.
Ion transport mechanisms for smoke inhalation injured airway epithelial barrier
Authors: Chang Jianjun , Chen Zaixing , Zhao Runzhen , Nie Hong-Guang , Ji Hong-Long
Published: March 2020

Smoke inhalation injury is the leading cause of death in firefighters and victims. Inhaled hot air and toxic smoke are the predominant hazards to the respiratory epithelium. We aimed to analyze the effects of thermal stress and smoke aldehyde on the permeability of the airway epithelial barrier. Transepithelial resistance (RTE) and short-circuit current (ISC) of mouse tracheal epithelial monolayers were digitized by an Ussing chamber setup. Zonula occludens-1 tight junctions were visualized under confocal microscopy. A cell viability test and fluorescein isothiocyanate-dextran assay were performed. Thermal stress (40°C) decreased RTEin a two-phase manner. Meanwhile, thermal stress increased ISCfollowed by its decline. Na+depletion, amiloride (an inhibitor for epithelial Na+channels [ENaCs]), ouabain (a blocker for Na+/K+-ATPase) and CFTRinh-172 (a blocker of cystic fibrosis transmembrane regulator [CFTR]) altered the responses of RTEand ISCto thermal stress. Steady-state 40°C increased activity of ENaCs, Na+/K+-ATPase, and CFTR. Acrolein, one of the main oxidative unsaturated aldehydes in fire smoke, eliminated RTEand ISC. Na+depletion, amiloride, ouabain, and CFTRinh-172 suppressed acrolein-sensitive ISC, but showed activating effects on acrolein-sensitive RTE. Thermal stress or acrolein disrupted zonula occludens-1 tight junctions, increased fluorescein isothiocyanate-dextran permeability but did not cause cell death or detachment. The synergistic effects of thermal stress and acrolein exacerbated the damage to monolayers. In conclusion, the paracellular pathway mediated by the tight junctions and the transcellular pathway mediated by active and passive ion transport pathways contribute to impairment of the airway epithelial barrier caused by thermal stress and acrolein.

Graphical Headlights

Thermal stress and acrolein are two essential determinants for smoke-inhalation injury, impairing airway epithelial barrier.

Transcellular ion transport pathways via the ENaC, CFTR, and Na/K-ATPase are interrupted by both thermal stress and acrolein, one of the most potent smoke toxins.

Heat and acrolein damage the integrity of the airway epithelium through suppressing and relocating the tight junctions.
A survey of rare epigenetic variation in 23,116 human genomes identifies disease-relevant epivariations and novel CGG expansions
Authors: Garg Paras , Jadhav Bharati , Rodriguez Oscar L. , Patel Nihir , Martin-Trujillo Alejandro , Jain Miten , Metsu Sofie , Olsen Hugh , Paten Benedict , Ritz Beate , Kooy R. Frank , Gecz Jozef , Sharp Andrew J.
Published: March 2020

There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals using the Illumina 450k array. Using a robust outlier approach, we identified 4,452 unique autosomal epivariations, including potentially inactivating promoter methylation events at 384 genes linked to human disease. For example, we observed promoter hypermethylation ofBRCA1andLDLRat population frequencies of ~1 in 3,000 and ~1 in 6,000 respectively, suggesting that epivariations may underlie a fraction of human disease which would be missed by purely sequence-based approaches. Using expression data, we confirmed that many epivariations are associated with outlier gene expression. Analysis of SNV data and monozygous twin pairs suggests that approximately two thirds of epivariations segregate in the population secondary to underlying sequence mutations, while one third are likely sproradic events that occur post-zygotically. We identified 25 loci where rare hypermethylation coincided with the presence of an unstable CGG tandem repeat, and validated the presence of novel CGG expansions at several of these, identifying the molecular defect underlying most of the known folate-sensitive fragile sites in the genome. Our study provides a catalog of rare epigenetic changes in the human genome, gives insight into the underlying origins and consequences of epivariations, and identifies many novel hypermethylated CGG repeat expansions.
Krüppel-Like Factor 14 Improves Cardiac Function After Myocardial Infarction
Authors: Wang Yating , Xu Danyan , Shen Li
Published: March 2020

Background

Reversal of heart failure after myocardial infarction (MI) remains a global challenge. The goal of a clinical physician is to prevent heart failure immediately following the infarct. Since traditional strategies are only partially helpful for improving cardiac function, there is an urgency to identify novel approaches to maintain cardiac function.

Objectives

The aim of this study was to determine the role of Krüppel-Like Factor 14 (KLF14) in the heart post-MI.

Methods and Results

Wild-type and KLF14 overexpression mice were subjected to MI. At four weeks following MI, the infarct size was significantly reduced, left ventricular fraction shortening was significantly preserved, and left ventricular chamber dilation was attenuated in the KLF14 overexpression group. Transmission electron microscopy studies revealed striking evidence of decreased mitochondrial damage in the KLF14 overexpression myocardium following MI. To gain insight into the underlying relationship between KLF14 and mitochondria, we examined a broad array of genes involved in mitochondrial function and found that KLF14 overexpression was involved in the decreased apoptosis of mitochondria induced by H2O2. This beneficial effect was associated with increased levels of PGC-1α.

Conclusions

These results demonstrate that KLF14 plays a critical protective role in the heart after MI by regulating mitochondrial function, which may be achieved by regulating PGC-1α.
A dynamic 6,000-year genetic history of Eurasia’s Eastern Steppe
Authors: Jeong Choongwon , Wang Ke , Wilkin Shevan , Taylor William Timothy Treal , Miller Bryan K. , Ulziibayar Sodnom , Stahl Raphaela , Chiovelli Chelsea , Bemmann Jan H. , Knolle Florian , Kradin Nikolay , Bazarov Bilikto A. , Miyagashev Denis A. , Konovalov Prokopiy B. , Zhambaltarova Elena , Miller Alicia Ventresca , Haak Wolfgang , Schiffels Stephan , Krause Johannes , Boivin Nicole , Myagmar Erdene , Hendy Jessica , Warinner Christina
Published: March 2020

The Eastern Eurasian Steppe was home to historic empires of nomadic pastoralists, including the Xiongnu and the Mongols. However, little is known about the region’s population history. Here we reveal its dynamic genetic history by analyzing new genome-wide data for 214 ancient individuals spanning 6,000 years. We identify a pastoralist expansion into Mongolia ca. 3000 BCE, and by the Late Bronze Age, Mongolian populations were biogeographically structured into three distinct groups, all practicing dairy pastoralism regardless of ancestry. The Xiongnu emerged from the mixing of these populations and those from surrounding regions. By comparison, the Mongols exhibit much higher Eastern Eurasian ancestry, resembling present-day Mongolic-speaking populations. Our results illuminate the complex interplay between genetic, sociopolitical, and cultural changes on the Eastern Steppe.
Chronic Interleukin-1 exposure triggers selective expansion ofCebpa-deficient multipotent hematopoietic progenitors
Authors: Higa Kelly C. , Goodspeed Andrew , Chavez James S. , Zaberezhnyy Vadym , Rabe Jennifer L. , Tenen Daniel G. , Pietras Eric M. , DeGregori James
Published: March 2020

The early events that drive hematologic disorders like clonal hematopoiesis, myelodysplastic syndrome, myeloproliferative neoplasm, and acute myeloid leukemia are not well understood. Most studies focus on the cell-intrinsic genetic changes that occur in these disorders and how they impact cell fate decisions. We consider how chronic exposure to the pro-inflammatory cytokine, interleukin-1β (IL-1β), impactsCebpa-deficient hematopoietic stem and progenitor cells (HSPC) in competitive settings. We surprisingly found thatCebpa-deficient HSPC did not have a hematopoietic cell intrinsic competitive advantage; rather chronic IL-1β exposure engendered potent selection forCebpaloss. Chronic IL-1β augments myeloid lineage output by activating differentiation and repressing stem cell gene expression programs in aCebpa-dependent manner. As a result,Cebpa-deficient HSPC are resistant to the pro-differentiative effects of chronic IL-1β, and competitively expand. These findings have important implications for the earliest events that drive hematologic disorders, suggesting that chronic inflammation could be an important driver of leukemogenesis and a potential target for intervention.

Higaet al. show that chronic interleukin-1β exposure primes hematopoietic stem and progenitor cells for myelopoiesis by upregulating myeloid differentiation programs and repressing stem gene programs in aCebpa-dependent manner. Consequently, interleukin-1 potently selects forCebpaloss in hematopoietic stem and progenitor cells.
The environmental stress response causes ribosome loss in aneuploid yeast cells
Authors: Terhorst Allegra , Sandikci Arzu , Keller Abigail , Whittaker Charles A. , Dunham Maitreya J. , Amon Angelika
Published: March 2020

Aneuploidy, a condition characterized by whole chromosome gains and losses, is often associated with significant cellular stress and decreased fitness. However, how cells respond to the aneuploid state has remained controversial. In aneuploid budding yeast, two opposing gene expression patterns have been reported: the “environmental stress response” (ESR) and the “common aneuploidy gene-expression” (CAGE) signature, in which many ESR genes are oppositely regulated. Here, we investigate and bring clarity to this controversy. We show that the CAGE signature is not an aneuploidy-specific gene expression signature but the result of normalizing the gene expression profile of actively proliferating aneuploid cells to that of euploid cells grown into stationary phase. Because growth into stationary phase is amongst the strongest inducers of the ESR, the ESR in aneuploid cells was masked when stationary phase euploid cells were used for normalization in transcriptomic studies. When exponentially growing euploid cells are used in gene expression comparisons with aneuploid cells, the CAGE signature is no longer evident in aneuploid cells. Instead, aneuploid cells exhibit the ESR. We further show that the ESR causes selective ribosome loss in aneuploid cells, providing an explanation for the decreased cellular density of aneuploid cells. We conclude that aneuploid budding yeast cells mount the ESR, rather than the CAGE signature, in response to aneuploidy-induced cellular stresses, resulting in selective ribosome loss. We propose that the ESR serves two purposes in aneuploid cells: protecting cells from aneuploidy-induced cellular stresses and preventing excessive cellular enlargement during slowed cell cycles by downregulating translation capacity.
The anti-tumour effect of CD8+ infiltration is associated with Human Leukocyte Antigen Class I expression and tumour proliferation in colorectal cancer
Authors: Powell Arfon G M T , Richards Colin , Platt Jonathan J , Orange Clare , Bennett Lindsay , McMillan Donald C , Horgan Paul G , Edwards Joanne
Published: March 2020

Purpose

The host inflammatory response is an important determinant of cancer outcome, however, the factor/s that regulate this response remains unclear. We aimed to determine if Human Leukocyte Antigen (HLA) class I and tumour cell proliferation are associated with CD8+ infiltration and survival in patients undergoing potentially curative resection for colorectal cancer.

Methods

HLA class I expression (W6/32 and B2-microglobulin) and tumour proliferation index (Ki67) were quantified using immunohistochemistry on tissue micro arrays (TMA). The local inflammatory response at the invasive margin was assessed using the Klintrup-Makinen (K-M) score and CD8+ infiltration was assessed at the invasive margin (mCD8+), stroma (sCD8+) and cancer cell nests (cCD8+).

Results

Preserved HLA class I expression was associated with lower Dukes’ stage (p=0.032), lower T stage (p=0.040) and higher cCD8+ (p=0.003). High Ki67 was associated with a good K-M score (p<0.001), higher mCD8+ (p=0.033), higher sCD8+ (p=0.025) and higher cCD8+ (p<0.001). On binary logistical regression analysis both preserved HLA class I expression (HR 1.99 95%CI (1.13–3.51),p=0.012) and high Ki67 (HR 2.63 95%CI (1.08–6.38),p=0.033) were independently associated with higher CD8+ infiltration within the cancer cell nests. On multivariate survival analysis, preserved HLA class I expression was associated with disease free (HR 0.47 95%CI (0.25–0.89),p=0.020) and cancer specific survival (HR 0.52 95%CI (0.28–0.97),p=0.038).

Conclusion

This study suggests that a pronounced local inflammatory response is independently associated with both, HLA class I expression and tumour proliferation.
An international comparison of the second derivative of COVID-19 deaths after implementation of social distancing measures
Authors: Pike W. T. , Saini V.
Published: March 2020

This work compares deaths for confirmed COVID-19 cases in China to eight other countries, Italy, Spain, France, USA, UK, Germany, Netherlands and South Korea. After implementing varying intensities and timing of social distancing measures, several appear to be converging onto the decline in the daily growth rate of deaths, or relative second derivative of total deaths, seen in China after the implementation an aggressive social distancing policy. By calculating future trajectories in these countries based on the observed Chinese fatality statistics, an estimate of the total deaths and maximum daily death rates over a defined period of time is made. Our lower bound estimate for the United Kingdom based on the real data approximates the lower bound estimate of the recent modelling study of Ferguson et al. [1]. These results suggest there may be a threshold of effective public health intervention. Our method of viewing the data may be helpful in monitoring the course of the epidemic, judging the effectiveness of implementation, and monitoring the relaxation of social distancing.
Coast-to-coast spread of SARS-CoV-2 in the United States revealed by genomic epidemiology
Authors: Fauver Joseph R. , Petrone Mary E. , Hodcroft Emma B. , Shioda Kayoko , Ehrlich Hanna Y. , Watts Alexander G. , Vogels Chantal B.F. , Brito Anderson F. , Alpert Tara , Muyombwe Anthony , Razeq Jafar , Downing Randy , Cheemarla Nagarjuna R. , Wyllie Anne L. , Kalinich Chaney C. , Ott Isabel , Quick Joshua , Loman Nicholas J. , Neugebauer Karla M. , Greninger Alexander L. , Jerome Keith R. , Roychoudhury Pavitra , Xie Hong , Shrestha Lasata , Huang Meei-Li , Pitzer Virginia E. , Iwasaki Akiko , Omer Saad B. , Khan Kamran , Bogoch Isaac I. , Martinello Richard A. , Foxman Ellen F. , Landry Marie L. , Neher Richard A. , Ko Albert I. , Grubaugh Nathan D.
Published: March 2020

Since its emergence and detection in Wuhan, China in late 2019, the novel coronavirus SARS-CoV-2 has spread to nearly every country around the world, resulting in hundreds of thousands of infections to date. The virus was first detected in the Pacific Northwest region of the United States in January, 2020, with subsequent COVID-19 outbreaks detected in all 50 states by early March. To uncover the sources of SARS-CoV-2 introductions and patterns of spread within the U.S., we sequenced nine viral genomes from early reported COVID-19 patients in Connecticut. Our phylogenetic analysis places the majority of these genomes with viruses sequenced from Washington state. By coupling our genomic data with domestic and international travel patterns, we show that early SARS-CoV-2 transmission in Connecticut was likely driven by domestic introductions. Moreover, the risk of domestic importation to Connecticut exceeded that of international importation by mid-March regardless of our estimated impacts of federal travel restrictions. This study provides evidence for widespread, sustained transmission of SARS-CoV-2 within the U.S. and highlights the critical need for local surveillance.
Revealing ecologically coherent population structure of uncultivated bacterioplankton with POGENOM
Authors: Sjöqvist C , Delgado Zambrano LF , Alneberg J , Andersson AF
Published: March 2020

Background

Bacterioplankton are main drivers of biogeochemical cycles and important components of aquatic food webs. However, difficulties in culturing the majority of aquatic prokaryotic species have complicated the study of their microdiversity. Here, we present POGENOM, a software that quantifies population genomic indices from metagenome data, enabling comparative analysis of genomic diversity and differentiation in multiple species in parallel. We demonstrate POGENOM on metagenome-assembled genomes from the Baltic Sea and investigate their genomic variation using metagenome data spanning a 1700 km transect and covering seasonal variation at one station.

Results

The majority of the investigated species, representing several major bacterioplankton clades, displayed population structure correlating significantly with environmental factors such as salinity, temperature, nutrients and oxygen, both over horizontal and vertical dimensions. Population differentiation was more pronounced over spatial than temporal scales, although some species displayed population structure correlating with season. We discovered genes that have undergone adaptation to different salinity regimes, potentially responsible for the populations’ existence along the salinity range.

Conclusions

We provide a new tool for high-throughput population genomics analysis based on metagenomics data. From an evolutionary point of view, our findings emphasize the importance of physiological barriers, and highlight the role of adaptive divergence as a structuring mechanism of bacterioplankton species, despite their seemingly unlimited dispersal potential. This is of central importance when learning about how species have adapted to new environmental conditions and what their adaptive potential is in the face of Global Change.
Telomere length heterogeneity in ALT cells is maintained by PML-dependent localization of the BTR complex to telomeres
Authors: Loe Taylor K. , Li Julia Su Zhou , Zhang Yuxiang , Azeroglu Benura , Boddy Michael Nicholas , Denchi Eros Lazzerini
Published: March 2020

Telomeres consist of TTAGGG repeats bound by protein complexes that serve to protect the natural end of linear chromosomes. Most cells maintain telomere repeat lengths by using the enzyme telomerase, although there are some cancer cells that use a telomerase-independent mechanism of telomere extension, termed alternative lengthening of telomeres (ALT). Cells that use ALT are characterized, in part, by the presence of specialized PML nuclear bodies called ALT-associated PML bodies (APBs). APBs localize to and cluster telomeric ends together with telomeric and DNA damage factors, which led to the proposal that these bodies act as a platform on which ALT can occur. However, the necessity of APBs and their function in the ALT pathway has remained unclear. Here, we used CRISPR/Cas9 to delete PML and APB components from ALT-positive cells to cleanly define the function of APBs in ALT. We found that PML is required for the ALT mechanism, and that this necessity stems from APBs’ role in localizing the BLM–TOP3A–RMI (BTR) complex to ALT telomere ends. Strikingly, recruitment of the BTR complex to telomeres in a PML-independent manner bypasses the need for PML in the ALT pathway, suggesting that BTR localization to telomeres is sufficient to sustain ALT activity.
Texture corrections for total scattering functions
Authors: Cervellino Antonio , Frison Ruggero
Published: March 2020

Many functional materials are today synthesized in the form of nanoparticles displaying preferred orientation effects to some small or large extent. The analysis of diffraction data of such kinds of systems is best performed in the framework of the total scattering approach that prescinds from translation symmetry assumptions. Therefore modified expressions were derived for the most common total scattering functions, in particular the Debye scattering equation (DSE) which yields the texture-averaged differential cross section as a function of atomic coordinates and texture parameters. The modified DSE encodes higher-order even spherical Bessel functions which account for the texture effect. Selection rules arising from experimental geometries and symmetries are discussed. In addition the duality of the texture effect is introduced showing the effects of texture on both the I(Q) and {\cal{G}}(r). The paper includes several definitions and appendices which are meant to be useful for those involved in the development of crystallographic computing.
Entropy generation analysis of multi-walled carbon nanotube dispersed nanoliquid in the presence of heat source through a vertical microchannel
Authors: Sindhu S. , Gireesha B.J. , Sowmya G.
Published: March 2020

Purpose

The influence of radiation on nanoliquid flow through a vertical microchannel in the presence of heat source is examined. This study aims to investigate the efficiency of multi-walled carbon nanotube (MWCNT) considering water and engine oil as base fluid.

Design/methodology/approach

Nondimensional variables are used to obtain the dimensionless physical model. The solutions are computed numerically via Runge–Kutta–Fehlberg integration scheme.

Findings

It is established that (knf/kf)Lamina > (knf/kf)Column > (knf/kf)Tetrahedron > (knf/kf)Hexahedron > (knf/kf)Sphere.

Originality/value

Thermal conductivity of MWCNT is analyzed using different models. Also, it is remarked that Xue model exhibits higher thermal conductivity for MWCNT compared to Maxwell model, Yu-Choi model and Hamilton-Crosser model.
The future of university or universities of the future: a paradox for uncertain times
Authors: Alexander Allen , Manolchev Constantine
Published: March 2020

Purpose

Using narratives from leading international academics and commentators, the authors chart four, possible, “universities of the future” models and discuss how current university management issues can enable or hinder them.

Design/methodology/approach

Deploying a Gioia methodology analysis of “University of the Future” narratives, the authors derive 12 categories of institutional properties and, ultimately, four distinct models.

Findings

The authors identify how current, classic and polytechnic institutions can adapt their operations and service delivery in order to transition into future-ready business models.

Originality/value

The authors interpret the opinions and predictions from world-leading experts in the higher education field in order to present the first, to our knowledge, typology of aspirational university models.
Gender, quality and health – a study of Swedish secondary school teachers
Authors: Lagrosen Yvonne , Lagrosen Stefan
Published: March 2020

Purpose

The purpose of this paper is to examine gender differences regarding the experience of workplace health and quality management. In this context, we include some factors of work environment that have previously been shown to be related to health such as workplace learning, stress, flow and sense of coherence.

Design/methodology/approach

A questionnaire based on previous research was constructed. It was delivered to a population of Swedish upper secondary school teachers. Three hundred eleven responses were returned. They were analysed for gender differences witht-tests and chi-square tests.

Findings

The results show that women's experience of their health is worse than men's despite having a generally better experience of the quality management values, workplace learning and flow. Moreover, women experience more stress, and they are more often subjected to sexual harassment while men more frequently had been exposed to physical violence.

Research limitations/implications

The study has implications for research in that it indicates that although women have better experiences of many of the factors that previous research has shown to be related to workplace health, their health is actually worse. A limitation is that the response rate was low.

Practical implications

The findings should be useful for managers attempting to improve the workplace health of their staff. The finding that women report less health than men even though experiencing quality management values more, means that women's health need a particular focus in secondary schools.

Originality/value

The connection between health and quality management has not been previously studied from a gender perspective.
Drivers and relationship benefits of customer willingness to engage in CSR initiatives
Authors: O'Brien Ingrid M. , Ouschan Robyn , Jarvis Wade , Soutar Geoffrey Norman
Published: March 2020

Purpose

The purpose of this paper is to assess the impact of CSR initiative preference, customer helping orientation and customer participation on willingness to engage in CSR and to demonstrate the influence this engagement has on their commitment and loyalty to the organisation.

Design/methodology/approach

This study entailed an online survey of customers from a large not-for-profit organisation (n = 210). Choice modelling is used to test a structural equation model of drivers and outcomes of willingness to engage in CSR.

Findings

Results demonstrate the CSR initiative preferred by customers has a stronger impact on their willingness to engage with the CSR initiative (volunteering their time, effort, money) than either customers' helping orientation or customer participation. Furthermore, willingness to engage in CSR influences customer commitment and loyalty to support and recommend the organisation.

Research limitations/implications

The results clearly demonstrate the significant impact that customers' preferences for and willingness to engage in CSR initiatives have on customers' relationship with not-for-profit organisations.

Social implications

The results highlight the importance of taking into account customer preferences for CSR issues to encourage customers to engage in CSR initiatives designed to benefit society.

Originality/value

Traditionally CSR literature has focused on how commercial firms' engagement in CSR creates value for the firm and society. The marketing literature has focused on how customer engagement in brand communities benefits the firm. This study extends the research by exploring customers’ willingness to engage in CSR with not-for-profit organisations. It uses Choice modelling to demonstrate the impact of customer preferences for local and aligned CSR initiatives on customer willingness to engage.
Conclusion: how is Malaysian hospitality and tourism education working with industry?
Authors: Hussain Kashif , Ragavan Neethiahnanthan Ari , Ming Vincent Tang Thien , Loong Chris Low Kam
Published: March 2020

Purpose

The purpose of this paper is to summarise the main points arising from the articles contained in this theme issue and to provide some directions for the future development of hospitality and tourism education in Malaysia.

Design/methodology/approach

The paper reviews the contribution made by this theme issue in response to the strategic question: How is Malaysian hospitality and tourism education working with the industry?

Findings

The paper observes that authors with different academic and industry backgrounds are able to generate significant outcomes in terms of the contribution to knowledge and/or professional practice, the implications for management action, applied research and industry practice in Malaysia.

Originality/value

This paper considers the extent to which the strategic question discussed in this theme issue could be applied to other ASEAN countries.