bluuebunny/crossref_metadata_2025 huggingface dataset:
The ketogenic diet is not effective in preclinical models of IDH1 wild-type and IDH1 mutant glioma
Authors: Javier Rodrigo , Horbinski Craig
Published: June 2020

Infiltrative gliomas are the most common neoplasms arising in the brain, and remain largely incurable despite decades of research. A subset of these gliomas contains mutations inisocitrate dehydrogenase 1(IDH1mut). This mutation disrupts cellular biochemistry, and IDH1mutgliomas are generally less aggressive than IDH1 wild-type (IDH1wt) gliomas. Some preclinical studies and clinical trials have suggested that a ketogenic diet (KD), characterized by low-carbohydrate and high-fat content, may be beneficial in slowing glioma progression. However, not all studies have shown promising results, and to date, no study has addressed whether IDH1mutgliomas might be more sensitive to KD. The aim of the current study was to compare the effects of KD in preclinical models of IDH1wtversus IDH1mutgliomas.In vitro, simulating KD by treatment with the ketone body β-hydroxybutyrate had no effect on the proliferation of patient-derived IDH1wtor IDH1mutglioma cells. Likewise, KD had no effect on thein vivogrowth of these patient-derived gliomas. Furthermore, mice engrafted with Sleeping-Beauty transposase-engineered IDH1wtand IDH1mutglioma showed no difference in survival while on KD. These data suggest that IDH1mutgliomas are not more responsive to KD, and that clinical trials further exploring KD in this subset of glioma patients may not be warranted.
Quantifying synergy in the bioassay-guided fractionation of natural product extracts
Authors: Dettweiler Micah , Marquez Lewis , Bao Max , Quave Cassandra L.
Published: June 2020

Mixtures of drugs often have greater therapeutic value than any of their constituent drugs alone, and such combination therapies are widely used to treat diseases such as cancer, malaria, and viral infections. However, developing useful drug mixtures is challenging due to complex interactions between drugs. Natural substances can be fruitful sources of useful drug mixtures because secondary metabolites produced by living organisms do not often act in isolationin vivo. In order to facilitate the study of interactions within natural substances, a new analytical method to quantify interactions using data generated in the process of bioassay-guided fractionation is presented here: the extract fractional inhibitory concentration index (EFICI). The EFICI method uses the framework of Loewe additivity to calculate fractional inhibitory concentration values by which interactions can be determined for any combination of fractions that make up a parent extract. The EFICI method was applied to data on the bioassay-guided fractionation ofLechea mucronataandSchinus terebinthifoliafor growth inhibition of the pathogenic bacteriumAcinetobacter baumannii. TheL. mucronataextract contained synergistic interactions (EFICI = 0.4181) and theS. terebinthifoliaextract was non-interactive overall (EFICI = 0.9129). Quantifying interactions in the bioassay-guided fractionation of natural substances does not require additional experiments and can be useful to guide the experimental process and to support the development of standardized extracts as botanical drugs.
Macrovesicular steatosis in nonalcoholic fatty liver disease is a consequence of purine nucleotide cycle driven fumarate accumulation
Authors: Sinton Matthew C. , Lucendo Villarin Baltasar , Meseguer Ripolles Jose , Wernig-Zorc Sara , Thomson John P. , Walker Paul D. , Thakker Alpesh , Lavery Gareth G. , Ludwig Christian , Tennant Daniel A. , Hay David C. , Drake Amanda J.
Published: June 2020

Nonalcoholic fatty liver disease (NAFLD) affects ~88% of obese individuals and is characterised by hepatic lipid accumulation. Mitochondrial metabolic dysfunction is a feature of NAFLD. We used a human pluripotent stem cell-based system to determine how mitochondrial dysfunction is linked to hepatic lipid accumulation. We induced lipid accumulation in hepatocyte-like cells (HLCs) using lactate, pyruvate and octanoate (LPO). Transcriptomic analysis revealed perturbation of mitochondrial respiratory pathways in LPO exposed cells. Using13C isotopic tracing, we identified truncation of the TCA cycle in steatotic HLCs. We show that increased purine nucleotide cycle (PNC) activity fuels fumarate accumulation and drives lipid accumulation in steatotic cells. These findings provide new insights into the pathogenesis of hepatic steatosis and may lead to an improved understanding of the metabolic and transcriptional rewiring associated with NAFLD.
Transposable elements are constantly exchanged by horizontal transfer reshaping mosquito genomes
Authors: de Melo Elverson Soares , Luz Wallau Gabriel da
Published: June 2020

Transposable elements (TEs) are a set of mobile elements within a genome. Due to their complexity, an in-depth TE characterization is only available for a handful of model organisms. In the present study, we performed ade novoand homology-based characterization of TEs in the genomes of 24 mosquito species and investigated their mode of inheritance. More than 40% of the genome ofAedes aegypti, Aedes albopictus, andCulex quinquefasciatusis composed of TEs, varying substantially amongAnophelesspecies (0.13%–19.55%). Class I TEs are the most abundant among mosquitoes and at least 24 TE superfamilies were found. Interestingly, TEs have been continuously exchanged by horizontal transfer (212 TE families of 18 different superfamilies) among mosquitoes since 30 million years ago, representing around 6% of the genome inAedesgenomes and a small fraction inAnophelesgenomes. Most of these horizontally transferred TEs are from the three ubiquitous LTR superfamilies: Gypsy, Bel-Pao and Copia. Searching more 32,000 genomes, we also uncover transfers between mosquitoes and two different Phyla—Cnidaria and Nematoda—and two subphyla—Chelicerata and Crustacea, identifying a vector, the wormWuchereria bancrofti, that enabled the horizontal spread of a Tc1-mariner element ofirritanssubfamily among variousAnophelesspecies. These data also allowed us to reconstruct the horizontal transfer network of this TE involving more than 40 species. In summary, our results suggest that TEs are constantly exchanged by common phenomena of horizontal transfers among mosquitoes, influencing genome variation and contributing to genome size expansion.

Author Summary

Most eukaryotes have DNA fragments inside their genome that can multiply by inserting themselves in other regions of the genome, generating variability. These fragments are called Transposable Elements (TEs). Since they are a constituent part of the eukaryote genomes, these pieces of DNA are usually inherited vertically by the offspring. To avoid damage to the genome caused by the replication and insertion of TEs, organisms usually control them, leading to their inactivation. However, TEs sometimes get out of control and invade other species through a horizontal transfer mechanism. This dynamic is not known in mosquitoes, a group of organisms that acts as vectors of many human diseases. We collected mosquito genomes available in public databases and characterized the whole content of TEs. Using a statistic supported method, we investigate TE relations among mosquitoes and discover that horizontal transfers of transposons are common and occurred in the last 30 million years among these species. Although not as common as transfers among closely related species, transposon transfer to distant species also occur. We also identify a parasite, a filarial worm, that may have facilitated the transfer of TE to many mosquitoes. Together, horizontally transferred TEs contribute to increasing mosquito genome size and variation.
The RNA-binding protein Igf2bp3 is critical for embryonic and germline development in zebrafish
Authors: Vong Yin Ho , Sivashanmugam Lavanya , Zaucker Andreas , Jones Alex , Sampath Karuna
Published: June 2020

The ability to reproduce is essential in all branches of life. In metazoans, this process is initiated by formation of the germline, a group of cells that are destined to form the future gonads, the tissue that will produce the gametes. The molecular mechanisms underlying germline formation differs between species. In zebrafish, development of the germline is dependent on the specification, migration and proliferation of progenitors called the primordial germ cells (PGCs). PGC specification is dependent on a maternally provided cytoplasmic complex of ribonucleoproteins (RNPs), the germplasm. Here, we show that the conserved RNA-binding protein (RBP), Igf2bp3, has an essential role during early embryonic development and germline development. Loss of Igf2bp3 leads to an expanded yolk syncytial layer (YSL) in early embryos, reduced germline RNA expression, and mis-regulated germline development. Maternal mutants affecting igf2bp3 exhibit abnormal PGCs and adult igf2bp3 mutants show male biased sex ratios. Therefore, Igf2bp3 is required for normal embryonic and germline development.
A highly stable, nondigestible lectin fromPomacea diffusaunveils clade-related protection systems in apple snail eggs
Authors: Brola TR , Dreon MS , Qiu JW , Heras H
Published: June 2020

The acquisition of egg protection is vital for species survival. Poisonous eggs fromPomaceaapple snails have defensive macromolecules for protection. Here we isolated and characterized a novel lectin called PdPV1 that is massively accumulated in the eggs ofPomacea diffusaand seems part of its protective cocktail. The native protein, an oligomer of ca. 256 kDa, has high structural stability, withstanding 15 min boiling and denaturing by sodium dodecyl sulphate. It resistsin vitroproteinase digestion and displays structural stability between pH 2.0–12.0 and up to 85 °C. These properties, as well as its subunit sequences, glycosylation pattern, presence of carotenoids, size, and global shape resemble those of its orthologs from otherPomacea. Further, like members of thecanaliculataclade, PdPV1 is recovered unchanged in faeces of mice ingesting it, supporting an antinutritive defensive function. PdPV1 also displays a strong hemagglutinating activity specifically recognizing selected ganglioside motifs with high affinity. This activity is only shared with PsSC, a perivitelline from the same clade (bridgesiiclade). As a whole, these results indicate that species in the genusPomaceahave diversified their eggs defences: Those from thebridgesiiclade are protected mostly by non-digestible lectins that lower the nutritional value of eggs, in contrast with protection by neurotoxins of otherPomaceaclades, indicating apple snail egg defensive strategies are clade-specific. The harsh gastrointestinal environment of predators would have favoured their appearance, extending by convergent evolution the presence of plant-like highly stable lectins, a strategy not reported in other animals.

Summary statement

Analysis of key snail egg proteins shows evolutionary defensive trends associated with the phylogenetic position, extending by convergent evolution the presence of plant-like defensive strategies not reported in other animals
An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19
Authors: Shrimp Jonathan H. , Kales Stephen C. , Sanderson Philip E. , Simeonov Anton , Shen Min , Hall Matthew D.
Published: June 2020

SARS-CoV-2 is the viral pathogen causing the COVID19 global pandemic. Consequently, much research has gone into the development of pre-clinical assays for the discovery of new or repurposing of FDA-approved therapies. Preventing viral entry into a host cell would be an effective antiviral strategy. One mechanism for SARS-CoV-2 entry occurs when the spike protein on the surface of SARS-CoV-2 binds to an ACE2 receptor followed by cleavage at two cut sites (“priming”) that causes a conformational change allowing for viral and host membrane fusion. TMPRSS2 has an extracellular protease domain capable of cleaving the spike protein to initiate membrane fusion. A validated inhibitor of TMPRSS2 protease activity would be a valuable tool for studying the impact TMPRSS2 has in viral entry and potentially be an effective antiviral therapeutic. To enable inhibitor discovery and profiling of FDA-approved therapeutics, we describe an assay for the biochemical screening of recombinant TMPRSS2 suitable for high throughput application. We demonstrate effectiveness to quantify inhibition down to subnanomolar concentrations by assessing the inhibition of camostat, nafamostat and gabexate, clinically approved agents in Japan. Also, we profiled a camostat metabolite, FOY-251, and bromhexine hydrochloride, an FDA-approved mucolytic cough suppressant. The rank order potency for the compounds tested are: nafamostat (IC50= 0.27 nM), camostat (IC50= 6.2 nM), FOY-251 (IC50= 33.3 nM) and gabexate (IC50= 130 nM). Bromhexine hydrochloride showed no inhibition of TMPRSS2. Further profiling of camostat, nafamostat and gabexate against a panel of recombinant proteases provides insight into selectivity and potency.
S1-Domain RNA-Binding Protein (CvfD) Is a New Post-Transcriptional Regulator That Mediates Cold Sensitivity, Phosphate Transport, and Virulence inStreptococcus pneumoniaeD39
Authors: Sinha Dhriti , Zheng Jiaqi J. , Tsui Ho-Ching Tiffany , Richardson John D. , De Lay Nicholas R. , Winkler Malcolm E.
Published: June 2020

Post-transcriptional gene regulation often involves RNA-binding proteins that modulate mRNA translation and/or stability either directly through protein-RNA interactions or indirectly by facilitating the annealing of small regulatory RNAs (sRNAs). The human pathogenStreptococcus pneumoniaeD39 (pneumococcus) does not encode homologs to RNA-binding proteins known to be involved in promoting sRNA stability and function, such as Hfq or ProQ, even though it contains genes for at least 112 sRNAs. However, the pneumococcal genome contains genes for other RNA-binding proteins, including at least six S1-domain proteins; ribosomal protein S1 (rpsA), polynucleotide phosphorylase(pnpA), RNase R (rnr), and three proteins of unknown functions. Here, we characterize the function of one of these conserved, yet uncharacterized S1-domain proteins, SPD_1366, which we have renamed CvfD (ConservedvirulencefactorD), since loss of this protein results in an attenuation of virulence in a murine pneumonia model. We report that deletion ofcvfDimpacts expression of 144 transcripts including thepst1operon, encoding the phosphate transport system 1 inS. pneumoniae. We further show that CvfD post-transcriptionally regulates the PhoU2 master regulator of the pneumococcal dual phosphate transport system by bindingphoU2mRNA and impacting PhoU2 translation. CvfD not only controls expression of phosphate transporter genes, but also functions as a pleiotropic regulator that impacts cold sensitivity and the expression of sRNAs and genes involved in diverse cellular functions, including manganese uptake and zinc efflux. Together, our data show that CvfD exerts a broad impact on pneumococcal physiology and virulence, partly by post-transcriptional gene regulation.

SIGNIFICANCE

Recent advances have led to the identification of numerous sRNAs in the major human respiratory pathogen,S. pneumoniae. However, little is known about the functions of most sRNAs or RNA-binding proteins involved in RNA biology in pneumococcus. In this paper, we characterize the phenotypes and one target of the S1-domain RNA-binding protein CvfD, a homolog of “general-stress protein 13” identified, but not extensively characterized in otherFirmicutespecies. Pneumococcal CvfD is a broadly pleiotropic regulator, whose absence results in misregulation of divalent cation homeostasis, reduced translation of the PhoU2 master regulator of phosphate uptake, altered metabolism and sRNA amounts, cold sensitivity, and attenuation of virulence. These findings underscore the critical roles of RNA biology in pneumococcal physiology and virulence.
Identification and characterization of centromeric sequences inXenopus laevis
Authors: Smith Owen K , Limouse Charles , Fryer Kelsey A , Teran Nicole A , Sundararajan Kousik , Heald Rebecca , Straight Aaron F
Published: June 2020

Centromeres play an essential function in cell division by specifying the site of kinetochore formation on each chromosome for mitotic spindle attachment. Centromeres are defined epigenetically by the histone H3 variant CEntromere Protein A (CENP-A). CENP-A nucleosomes maintain the centromere by designating the site for new CENP-A assembly after dilution by replication. Vertebrate centromeres assemble on tandem arrays of repetitive sequences but the function of repeat DNA in centromere formation has been challenging to dissect due to the difficulty in manipulating centromeres in cells.Xenopus laevisegg extracts assemble centromeresin vitro, providing a system for studying centromeric DNA functions. However, centromeric sequences inX. laevishave not been extensively characterized. In this study we combine CENP-A ChIP-seq with a k-mer based analysis approach to identify theX. laeviscentromere repeat sequences. Byin situhybridization we show thatX. laeviscentromeres contain diverse repeat sequences and we map the centromere position on eachX. laevischromosome using the distribution of centromere enriched k-mers. Our identification ofX. laeviscentromere sequences enables previously unapproachable centromere genomic studies. Our approach should be broadly applicable for the analysis of centromere and other repetitive sequences in any organism.
Super LeArner Prediction of NAb Panels (SLAPNAP): A Containerized Tool for Predicting Combination Monoclonal Broadly Neutralizing Antibody Sensitivity
Authors: Benkeser D , Williamson BD , Magaret CA , Nizam S , Gilbert PB
Published: June 2020

Single broadly neutralizing antibody (bnAb) regimens are currently being evaluated in randomized trials for prevention efficacy against HIV-1 infection. Subsequent trials will evaluate combination bnAb regimens (e.g., cocktails, multi-specific antibodies), which demonstrate higher potency and breadth in vitro compared to single bnAbs. Given the large number of potential regimens in the research pipeline, methods for down-selecting these regimens into efficacy trials are of great interest. To aid the down-selection process, we developed Super LeArner Prediction of NAb Panels (SLAPNAP), a software tool for training and evaluating machine learning models that predict in vitro neutralization resistance of HIV Envelope pseudoviruses to a given single or combination bnAb regimen, based on Envelope amino acid sequence features. SLAPNAP also provides measures of variable importance of sequence features. These results can rank bnAb regimens by their potential prevention efficacy and aid assessments of how prevention efficacy depends on sequence features.

Availability and Implementation

SLAPNAP is a freely available docker image that can be downloaded from DockerHub (https://hub.docker.com/r/slapnap/slapnap). Source code and documentation are available at GitHub (respectively,https://github.com/benkeser/slapnapandhttps://benkeser.github.io/slapnap/).

Contact

David Benkeser,benkeser@emory.edu
Response preparation involves a release of intracortical inhibition in task-irrelevant muscles
Authors: Gomez Isaac N. , Ormiston Kara , Greenhouse Ian
Published: June 2020

Action preparation involves widespread modulation of motor system excitability, but the precise mechanisms are unknown. In this study, we investigated whether intracortical inhibition changes in task-irrelevant muscle representations during action preparation. We used transcranial magnetic stimulation (TMS) combined with electromyography in healthy human adults to measure motor evoked potentials (MEPs) and cortical silent periods (CSPs) in task-irrelevant muscles during the preparatory period of simple delayed response tasks. In Experiment 1, participants responded with the left-index finger in one task condition and the right-index finger in another task condition, while MEPs and CSPs were measured from the contralateral non-responding and tonically contracted index finger. During Experiment 2, participants responded with the right pinky finger while MEPs and CSPs were measured from the tonically contracted left-index finger. In both experiments, MEPs and CSPs were compared between the task preparatory period and a resting intertrial baseline. The CSP duration during response preparation decreased from baseline in every case. A laterality difference was also observed in Experiment 1, with a greater CSP reduction during the preparation of left finger responses compared to right finger responses. MEP amplitudes showed no modulation during movement preparation in any of the three response conditions. These findings indicate cortical inhibition associated with task-irrelevant muscles is transiently released during action preparation and implicate a novel mechanism for the controlled and coordinated release of motor cortex inhibition.

New & Noteworthy

In this study we observed the first evidence of a release of intracortical inhibition in task-irrelevant muscle representations during response preparation. We applied transcranial magnetic stimulation to elicit cortical silent periods in task-irrelevant muscles during response preparation and observed a consistent decrease in the silent period duration relative to a resting baseline. These findings address the question of whether cortical mechanisms underlie widespread modulation in motor excitability during response preparation.
Visual mismatch responses index surprise signalling but not expectation suppression
Authors: Feuerriegel Daniel , Yook Jane , Quek Genevieve L. , Hogendoorn Hinze , Bode Stefan
Published: June 2020

The ability to distinguish between commonplace and unusual sensory events is critical for efficient learning and adaptive behaviour. This has been investigated using oddball designs in which sequences of often-appearing (i.e. expected) stimuli are interspersed with rare (i.e. surprising) deviants. Resulting differences in electrophysiological responses following surprising compared to expected stimuli are known as visual mismatch responses (VMRs). VMRs are thought to index co-occurring contributions of stimulus repetition effects, expectation suppression (that occurs when one’s expectations are fulfilled), and expectation violation (i.e. surprise) responses; however, these different effects have been conflated in existing oddball designs. To better isolate and quantify effects of expectation suppression and surprise, we adapted an oddball design based on Fast Periodic Visual Stimulation (FPVS) that controls for stimulus repetition effects. We recorded electroencephalography (EEG) while participants (N=48) viewed stimulation sequences in which a single face identity was periodically presented at 6 Hz. Critically, one of two different face identities (termed oddballs) appeared as every 7th image throughout the sequence. The presentation probabilities of each oddball image within a sequence varied between 10-90%, such that participants could form expectations about which oddball face identity was more likely to appear within each sequence. We also included ‘expectation neutral’ 50% probability sequences, whereby consistently biased expectations would not be formed for either oddball face identity. We found that VMRs indexed surprise responses, and effects of expectation suppression were absent. That is, ERPs were more negative-going at occipitoparietal electrodes for surprising compared to neutral oddballs, but did not differ between expected and neutral oddballs. Surprising oddball-evoked ERPs were also highly similar across the 10-40% appearance probability conditions. Our findings indicate that VMRs which are not accounted for by repetition effects are best described as an all-or-none surprise response, rather than a minimisation of prediction error responses associated with expectation suppression.

Highlights

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We used a recently-developed oddball design that controls for repetition effects

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We found effects of surprise but not expectation suppression on ERPs

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Surprise responses did not vary by stimulus appearance probability
Condensation tendency of connected contractile tissue with planar isotropic actin network
Authors: Xie Tianfa , Pierre Sarah R. St. , Olaranont Nonthakorn , Brown Lauren E. , Wu Min , Sun Yubing
Published: June 2020

It has been found that many types of cells form nematic symmetry on confined planar substrates. Such observation has been satisfactorily explained by modeling cells as crowded self-propelled rods. In this work, we report that rat embryonic fibroblast (REF) cells when confined in circular mesoscale patterns, form a new type of symmetry where cells align radially at the boundary. Unlike NIH-3T3 and MDCK monolayers, the REF monolayer presents a supracellular actin gradient with isotropic meshwork. In addition, the contractile REF cells present strong adhesive interactions with neighboring cells, which confers the monolayer with significant condensation tendency. We found the loss of condensation tendency by inhibiting the cell contractility or disrupting cell-cell adhesion led to the disappearance of the radial alignment. In theory, we found the prestretch due to condensation tendency with differential cell stiffness is sufficient to explain the new symmetry within a confined tissue continuum.
Development and Validation of a web-based Postoperative Clostridioides difficile infection risk prediction model
Authors: Woo Sang H. , Hess Bryan , Ackermann Lily , Cowan Scott W. , Valentine Jennifer
Published: June 2020

Background

Clostridioides difficile infection is associated with significant morbidity, mortality and increased costs. Assessment of the postoperative C. difficile infection risk is necessary to improve the outcome of surgical patients.

Objective

To develop and validate a risk prediction tool for C. difficile infection after surgery.

Methods

In this retrospective cohort study, 2,451,169 surgical patients from the American College of Surgeons National Surgical Quality Improvement Program Database (ACS-NSQIP) over 2015-2017 were included. Nine predictors were selected for the model: age, preoperative leukocytosis (>12 ×109/L), hematocrit (≤30%), chronic dialysis, insulin dependent diabetes, weight loss, steroid use, presence of preoperative sepsis, and surgery type. A second model included hospital length of stay as a predictor. A predictive model was developed using ACS-NSQIP 2015-2016 training cohort (n=1,435,157) and tested using 2017 validation cohort (n=1,016,012). Multivariate logistic regression was used for the model.

Main outcome

The primary outcome was postoperative 30-day C. difficile infection (CDI).

Results

0.39% of the patients (n=9,675) developed CDI and 42.3% (n=4,091) of CDI occurred post-discharge. The Clostridioides difficile risk prediction model had excellent AUC (area under the receiver operating characteristic curve) for postoperative C. difficile infection (training cohort=0.804, test cohort= 0.803). The model that includes hospital length of stay has a high AUC (training cohort=0.841, test cohort=0.838).

Conclusion

The C. difficile prediction model provides a robust predictive tool for postoperative C. difficile infection.
Genetic association of primary non-response to Anti-TNFα therapy in patients with Inflammatory Bowel Disease
Authors: De T. , Zhang H. , Alarcon C. , Lec B. , Avitia J. , Smithberger E. , Chen Chuyu , Horvath M. , Kwan S. , Young M. , Adhikari S. , Kwon J. H. , Pacheco J. , Jarvik G.P. , Wei W. , Mentch F. , Hakonarson H. , Sleiman P. , Gordon A.S. , Harley J. , Linneman J. G. , Hebbring S. , Parisiadou L. , Perera M. A.
Published: June 2020

Background & Aims

Primary non-response (PNR) to anti-tumor necrosis factor-α (TNFα) biologics is a serious concern in patients with inflammatory bowel disease (IBD). We aimed to identify the genetic variants associated with PNR.

Methods

Patients were recruited from outpatient GI clinics and PNR was determined using both clinical and endoscopic findings. A case-control genome-wide association study was performed in 589 IBD patients and associations were replicated in an independent cohort of 293 patients. Effect of the associated variant on gene expression and TNFα secretion was assessed by cell-based assays. Pleiotropic effects were investigated by Phenome-wide Association Study (PheWAS).

Results

We identified rs34767465 as associated with PNR to anti-TNF-α therapy (OR:2.07, 95%CI:1.46-2.94, p=2.43×10−7, [Replication OR:1.8, 95%CI:1.04-3.16, p=0.03]). rs34767465 is a multiple-tissue expression quantitative trait loci for FAM114A2. Using RNA-sequencing and protein quantification from HapMap lymphoblastoid cell lines (LCLs), we found a significant decrease in FAM114A2 mRNA and protein expression in both heterozygous and homozygous genotypes when compared to wild type LCLs. TNF-α secretion was significantly higher in THP-1 cells [differentiated into macrophages] with FAM114A2 knockdown versus controls. Immunoblotting experiments showed that depletion of FAM114A2 impaired autophagy related pathway genes suggesting autophagy mediated TNF-α secretion as a potential mechanism. PheWAS showed rs34767465 was associated with comorbid conditions found in IBD patients (derangement of joints [p=2.3×10−4], pigmentary iris degeneration [p=5.1×10−4], diverticulum of esophagus [p=6.3×10−4]).

Conclusion

We identified a variant rs34767465 associated with PNR to anti-TNFα biologics, which increases TNFα secretion through mechanism related to autophagy. rs34767465 may also explain the comorbidities associated with IBD.
Mutant glucocorticoid receptor binding elements on Interleukin-6 promoter regulate dexamethasone effects
Authors: Chang Wen-Teng , Hong Ming-Yuan , Chen Chien-Liang , Tsai Cheng-Chieh , Hwang Chi-Yuan , Chuang Chia-Chang
Published: June 2020

Glucocorticoid has been widely used as an important modulator for clinical infectious and inflammatory disease. Glucocorticoid receptor (GR) is a transcription factor belonging to the family of nuclear receptors, regulated anti-inflammatory process and the release of pro-inflammatory cytokines. Five putative GR and other transcription factor binding sites on interleukin (IL)-6 promoter were identified and dexamethasone could reduce LPS-induced IL-6 release. Among them, the mutant transcriptional factors NF-κB, AP-1, and Sp1-2 site decreased the basal and effects of lipopolysaccharide (LPS)-induced IL-6 promoter activities in different responses. GR2/3 seemed to be an important role in both basal and inducible promoter activities in LPS-induced inflammation. We concluded that the selective GR2/3 modulators may have agonistic and antagonistic combined effects and activate important signaling pathway during LPS-stimulated inflammatory process.
Incidence, Risk Factors and Mortality Outcome in Patients with Acute Kidney Injury in COVID-19: A Single-Center Observational Study
Authors: Gaetano Alfano , Annachiara Ferrari , Francesco Fontana , Giacomo Mori , Riccardo Magistroni , Marianna Meschiari , Erica Franceschini , Marianna Menozzi , Gianluca Cuomo , Gabriella Orlando , Antonella Santoro , Margherita Di Gaetano , Cinzia Puzzolante , Federica Carli , Andrea Bedini , Jovana Milic , Paolo Raggi , Massimo Girardis , Cristina Mussini , Gianni Cappelli , Giovanni Guaraldi ,   for the Modena Covid-19 Working Group (MoCo19)
Published: June 2020

Background

Acute kidney injury (AKI) is a recently recognized complication of coronavirus disease-2019 (COVID-19). This study aims to evaluate the incidence, risk factors and case-fatality rate of AKI in patients with documented COVID-19.

Methods

We reviewed the health medical records of 307 consecutive patients hospitalized for symptoms of COVID-19 at the University Hospital of Modena, Italy.

Results

AKI was diagnosed in 69 out of 307 (22.4%) patients. The stages of AKI were stage 1 in 57.9%, stage 2 in 24.6% and stage 3 in 17.3%. Hemodialysis was performed in 7.2% of the subjects. AKI patients had a mean age of 74.7±9.9 years and higher serum levels of the main marker of inflammation and organ involvement (lung, liver, hearth and liver) than non-AKI patients. AKI events were more frequent in subjects with severe lung comprise. Two peaks of AKI events coincided with in-hospital admission and death of the patients. Kidney injury was associate with a higher rate of urinary abnormalities including proteinuria (0.448±0.85 vs 0.18±0.29; P=<0.0001) and hematuria (P=0.032) compared to non-AKI patients. At the end of follow-up, 65.2% of the patients did not recover their renal function after AKI. Risk factors for kidney injury were age, male sex, CKD and non-renal SOFA. Adjusted Cox regression analysis revealed that AKI was independently associated with in-hospital death (hazard ratio [HR]=3.74; CI 95%, 1.34-10.46) compared to non-AKI patients. Groups of patients with AKI stage 2-3 and failure to recover kidney function were associated with the highest risk of in-hospital mortality. Lastly, long-hospitalization was positively associated with a decrease of serum creatinine, likely due to muscle depletion occurred with prolonged bed rest.

Conclusions

AKI was a dire consequence of patients with COVID-19. Identification of patients at high-risk for AKI and prevention of kidney injury by avoiding dehydration and nephrotoxic agents is imperative in this vulnerable cohort of patients.
Randomized Re-Opening of Training Facilities during the COVID-19 pandemic
Authors:   The TRAiN study group, Helsingen Lise M. , Løberg Magnus , Refsum Erle , Gjøstein Dagrun Kyte , Wieszczy Paulina , Olsvik Ørjan , Juul Frederik E. , Barua Ishita , Jodal Henriette C. , Herfindal Magnhild , Mori Yuichi , Jore Solveig , Lund-Johansen Fridtjof , Fretheim Atle , Bretthauer Michael , Kalager Mette
Published: June 2020

Background

Most countries closed training facilities during the COVID-19 pandemic. This may have negative consequences for people’s health and wellbeing. We investigated SARS-CoV-2 virus transmission and COVID-19 disease attributable to training facilities.

Methods

We randomized members 18 to 64 years with no COVID-19 relevant comorbidities randomized Five training facilities in Oslo, Norway to access or no access to their training facility. Facilities were opened from May 22, 2020 for individuals randomized to training, applying increased social distancing (1 meter for floor exercise, 2 meters for high-intensity classes), enhanced hand and surface hygiene. Locker rooms were open, showers and saunas were closed. We measured SARS-CoV-2 PCR status by self-administered naso-, oropharyngeal and sputum sampling after two weeks and clinical disease by linkage to electronic patient records after three weeks.

Results

3,764 individuals were randomized and included in analyses; 1,896 in the training and 1,868 in no-training arms. In the training arm, 81.8% trained at least once at the facilities, and 38.5% trained ≥six times. Out of 3,016 individuals who returned the SARS-CoV-2 PCR tests (80.5%), there was one positive test. The positive individual was randomized to training, but had not used the facility before testing day. Contact tracing revealed the workplace as transmission source. A total of 106 individuals (2.8%) had outpatient hospital visits, and six individuals were admitted to hospital during the three weeks after intervention start, with no differences between arms. There were no outpatient visits or hospital admissions due to COVID-19 in either group.

Conclusions

Provided good hygiene and social distancing measures, there was no increased COVID-19 spread at training facilities. NCT04406909
Seroprevalence of SARS-CoV-2 significantly varies with age: preliminary results from a mass population screening
Authors: Pagani Gabriele , Conti Federico , Giacomelli Andrea , Bernacchia Dario , Rondanin Rossana , Prina Andrea , Scolari Vittore , Gandolfi Cecilia Eugenia , Castaldi Silvana , Marano Giuseppe , Ottomano Cosimo , Boracchi Patrizia , Biganzoli Elia , Galli Massimo
Published: June 2020

Objectives

Castiglione D’Adda is one of the municipalities more precociously and severely affected by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) epidemic in Lombardy. With our study we aimed to understand the diffusion of the infection by mass seroprevalence screening.

Methods

We searched for SARS-CoV-2 IgGs in the entire voluntary population using lateral flow immune-cromatographic tests on capillary blood (rapid tests). We then performed chemioluminescent serological assays (CLIA) and naso-pharyngeal swabs in a randomized representative sample of 562 subjects and in every subject with a positive rapid test.

Results

Based on CLIA serologies on the representative random sample (509 subjects), we estimated a 23% IgG seroprevalence. We also found a strong correlation between age and prevalence, with the elderly showing the highest probability of a positive serological test.

Conclusions

In an area of unrestricted viral circulation less than one-fourth of the population tested positive for SARS-CoV-2 IgG. Seroprevalence increased with increasing age, possibly suggesting differences in susceptibility to the infection.
Untangling the effects of cellular composition on coexpression analysis
Authors: Farahbod Marjan , Pavlidis Paul
Published: June 2020

Coexpression analysis is widely used for inferring regulatory networks, predicting gene function, and interpretation of transcriptome profiling studies, based on methods such as clustering. The majority of such studies use data collected from bulk tissue, where the effects of cellular composition present a potential confound. However, the impact of composition on coexpression analysis has not been studied in detail. Here, we examine this issue for the case of human RNA analysis. Focusing on brain tissue, we found that, for most genes, differences in expression levels across cell types account for a large fraction of the variance of their measured RNA levels (median R2 = 0.68). We then show that genes that have similar expression patterns across cell types will have correlated RNA levels in bulk tissue, due to the effect of variation in cellular composition. We demonstrate that much of the coexpression and the formation of coexpression clusters can be attributed to this effect for both brain and blood transcriptomes. For brain, we further show how this composition-induced coexpression masks underlying intra-cell-type coexpression observed in single-cell data. An attempt to correct for composition yielded mixed results. Our conclusion is that the dominant coexpression signal in brain, blood, and, likely, other complex tissues can be attributed to cellular compositional effects, rather than intra-cell-type regulatory relationships. These results have implications for the relevance and interpretation of coexpression analysis.
Effect of different laser energy densities on the corrosion resistance of aluminum alloys
Authors: Xie Di , Chen Hui , Yin Siyi , Wang Feisen , Chen Jingwen , Ai Sifei
Published: June 2020

Purpose

Laser cleaning, as a new type of cleaning technology, has the advantages of environment-friendliness, better selectivity, better controllability and higher efficiency compared to traditional chemical cleaning or grinding. This paper aims to use ultra-fast surface laser cleaning equipment built in laboratory to study the influence of different energy density (7.6, 11.5 and 15.3 J/cm2) on corrosion resistance of the aluminum alloy A7N01P-T4, a high-speed train body material.

Design/methodology/approach

SEM, white light interferometer, EDS and XPS were used to analyze the surface morphology, roughness, element content and oxide layer composition of aluminum alloy before and after cleaning. The corrosion resistance was studied by electrochemical experiments and exfoliation corrosion experiments.

Findings

The results showed that new oxide scale was formed on the surface after laser cleaning. The changes of surface roughness and chemical composition of oxide scale made a significant influence on corrosion behaviors. Better corrosion resistance was obtained with the energy density increased, and at the energy density of 11.5 J/cm2, aluminum alloy exhibited the best corrosion resistance.

Research limitations/implications

The paper only studies specific aluminum alloys and is not universal. Laser cleaning equipment is set up for the laboratory and has not yet been put into industrial production.

Practical implications

This paper indicated that ultra-fast laser processing was a new direction for the development of industrial equipment surface cleaning and carried out ultra-fast laser of aluminum alloy surface cleaning had certain research significance for its corrosion resistance.

Social implications

Compared with the conventional cleaning methods such as air abrasives grinding or chemical cleaning, laser cleaning has advantages of environment-friendliness, better selectivity, better controllability and higher efficiency. Laser cleaning can not only protect the environment, but also improve cleaning efficiency.

Originality/value

Changes in the surface of aluminum alloys after ultra-fast surface laser treatment were found, and the mechanism of changes in aluminum alloy corrosion properties was clarified.
Identifying organizational variables to the implementation of horizontal strategy in conglomerates
Authors: Verma Pratima , Sharma R.R.K. , Kumar Vimal , Hsu Sung Chi , Lai Kuei-Kuei
Published: June 2020

Purpose

The paper aims to investigate organizational variables and develop their relationship with horizontal strategy. The cultural dimensions and organization structure have been considered as organizational variables. The study also aims to shed light on the implementation horizontal strategy in conglomerates.

Design/methodology/approach

A survey was carried out with 122 conglomerate firms for examination. These companies were chosen to be of different sizes and sectors. The multiple regression analysis was utilized to analyze the data.

Findings

The results reveal that conglomerate firms also have a horizontal strategy. Additionally, organizational cultural dimensions namely, collectivism, clan culture, market culture and long-term orientation; formal and informal relationship; and horizontal organization structure (HOS) have positive and significant relationship with horizontal strategy. No significant relationship was found between uncertainty avoidance and adhocracy culture, and horizontal strategy.

Research limitations/implications

The major contributions of this study are explicitly identified as horizontal strategy exists in the conglomerate firms where the few organizational variables play a significant role in horizontal strategy implementation.

Originality/value

This study has been done in an effort to make supporting guidelines to fill the gaps in conglomerate firms. This study offers an effective role of cultural dimensions and structure as drivers of horizontal strategy implementation, and this study spells out and extends the literature and proposes a conceptual framework.
How to prevent a global food and nutrition security crisis under COVID-19?
Authors: Fan Shenggen , Si Wei , Zhang Yumei
Published: June 2020

Purpose

The purposes of this paper are to review the impact on food and nutrition security of several pandemic emergencies and the 2018 food price crisis from a global perspective, examine the Chinese experiences and lessons in ensuring food and nutrition security for its citizen and propose policy actions to prevent a global food and nutrition security crisis.

Design/methodology/approach

The authors utilize a noncomprehensive review of peer-reviewed and nonpeer-reviewed literature, as well as a case study approach.

Findings

Under the ongoing COVID-19, China's food and nutrition are relatively secure in short run largely due to governmental proactive policies but may face uncertainties in livestock production and imports of soybean in the medium and long terms. Given that the disease has spread to almost all countries in the world, global cooperation and coordination are needed to prevent systemic risks to global food and nutrition security.

Practical implications

The review and analysis of this paper will help policymakers in China and other countries to design strategies and actions to prevent food and nutrition security crisis under the ongoing COVID-19 emergency and other similar threats in the future.

Originality/value

This paper provides recommendations to prevent food and nutrition security crisis based on data, evidence and case studies.
Overcoming hierarchy in business model innovation: an actor-oriented approach
Authors: Di Toma Paolo , Ghinoi Stefano
Published: June 2020

Purpose

Business model innovation is a key element for firms' competitiveness. Its development can be supported by the establishment of an actor-oriented scheme to overcome hierarchical structures. The actor-oriented scheme is characterized by intra-organizational networks of relationships that can be established and dissolved between individuals. However, we lack an empirical perspective about its establishment; therefore, the purpose of this research is to advance our understanding of intra-organizational networks for supporting business model innovation.

Design/methodology/approach

Individuals create and manage knowledge aimed to innovate the business model through cognitive search and experiential learning mechanisms. Knowledge is spread within organizations by using intra-organizational advice networks, whose patterns reflect the presence of an actor-oriented scheme. This work applies social network analysis to network data from a multi-unit organization specializing in personal care services. We use a Logistic Regression-Quadratic Assignment Procedure to analyze intra-organizational network data on managers' advice exchange related to the learning modes of cognitive search and experiential learning.

Findings

Our research empirically identifies the main elements of an actor-oriented scheme in a business model innovation process. We find that managers are able to self-organize, because they are not influenced by their organizational roles, and that commons for sharing resources and protocols, processes and infrastructures enable advice exchange, thus showing the presence of an actor-oriented scheme in business model innovation process.

Research limitations/implications

This research is based on a cross-sectional database. A longitudinal study would provide a better understanding of the network evolution characterizing the innovation process.

Practical implications

The results of our study support organizational decision-making for business model innovation.

Originality/value

This study provides empirical evidence of how an actor-oriented scheme emerges in a business model innovation process.