bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of drugs associated with reduced severity of COVID-19: A case-control study in a large population
Authors: Israel Ariel , Schäffer Alejandro A. , Cicurel Assi , Feldhamer Ilan , Tal Ameer , Cheng Kuoyuan , Sinha Sanju , Schiff Eyal , Lavie Gil , Ruppin Eytan
Published: October 2020

Background

Until COVID-19 drugs specifically developed to treat COVID-19 become more widely accessible, it is crucial to identify whether existing medications have a protective effect against severe disease. Towards this objective, we conducted a large population study in Clalit Health Services (CHS), the largest healthcare provider in Israel, insuring over 4.7 million members.

Methods

Two case-control matched cohorts were assembled to assess which medications, acquired in the last month, decreased the risk of COVID-19 hospitalization. Case patients were adults aged 18-95 hospitalized for COVID-19. In the first cohort, five control patients, from the general population, were matched to each case (n=6202); in the second cohort, two non-hospitalized SARS-CoV-2 positive control patients were matched to each case (n=6919). The outcome measures for a medication were: odds ratio (OR) for hospitalization, 95% confidence interval (CI), and the p-value, using Fisher’s exact test. False discovery rate was used to adjust for multiple testing.

Results

Medications associated with most significantly reduced odds for COVID-19 hospitalization include: ubiquinone (OR=0.185, 95% CI (0.058 to 0.458), p<0.001), ezetimibe (OR=0.488, 95% CI ((0.377 to 0.622)), p<0.001), rosuvastatin (OR=0.673, 95% CI (0.596 to 0.758), p<0.001), flecainide (OR=0.301, 95% CI (0.118 to 0.641), p<0.001), and vitamin D (OR=0.869, 95% CI (0.792 to 0.954), p<0.003). Remarkably, acquisition of artificial tears, eye care wipes, and several ophthalmological products were also associated with decreased risk for hospitalization.

Conclusions

Ubiquinone, ezetimibe and rosuvastatin, all related to the cholesterol synthesis pathway were associated with reduced hospitalization risk. These findings point to a promising protective effect which should be further investigated in controlled, prospective studies.

Funding

This research was supported in part by the Intramural Research Program of the National Institutes of Health, NCI.
A Highly Generalizable Natural Language Processing Algorithm for the Diagnosis of Pulmonary Embolism from Radiology Reports
Authors: Johnson Jacob , Qiu Grace , Lamoureux Christine , Ngo Jennifer , Ngo Lawrence
Published: October 2020

Though sophisticated algorithms have been developed for the classification of free-text radiology reports for pulmonary embolism (PE), their overall generalizability remains unvalidated given limitations in sample size and data homogeneity. We developed and validated a highly generalizable deep-learning based NLP algorithm for this purpose with data sourced from over 2,000 hospital sites and 500 radiologists. The algorithm achieved an AUCROC of 0.995 on chest angiography studies and 0.994 on non-angiography studies for the presence or absence of PE. The high accuracy achieved on this large and heterogeneous dataset allows for the possibility of application in large multi-center radiology practices as well as for deployment at novel sites without significant degradation in performance.
Genetics of Low Polygenic Risk Score Type 1 Diabetes Patients: rare variants in 22 novel loci
Authors: Qu Jingchun , Qu Hui-Qi , Bradfield Jonathan , Glessner Joseph , Chang Xiao , Tian Lifeng , March Michael , Roizen Jeffrey D , Sleiman Patrick , Hakonarson Hakon
Published: October 2020

With polygenic risk score (PRS) for autoimmune type 1 diabetes (T1D), this study identified T1D cases with low T1D PRS and searched for susceptibility loci in these cases. Our hypothesis is that genetic effects (likely mediated by relatively rare genetic variants) of non-mainstream (or non-autoimmune) T1D might have been diluted in the previous studies on T1D cases in general. Two cohorts for the PRS modeling and testing respectively were included. The first cohort consisted of 3,356 T1D cases and 6,203 controls, and the independent second cohort consisted of 3,355 T1D cases and 6,203 controls. Cases with low T1D PRS were identified using PRSice-2 and compared to controls with low T1D PRS by genome-wide association (GWA) test. Twenty-six genetic loci with SNPs/SNVs associated with low PRS T1D at genome-wide significance (P≤5.0xE-08) were identified, including 4 established T1D loci, as well as 22 novel loci represented by rare SNVs. For the 22 novel loci, 12 regions have been reported of association with obesity related traits by previous GWA studies. Five loci encoding long intergenic non-protein coding RNAs (lncRNA), two loci involved in N-linked glycosylation, two loci encoding GTPase activators, and two ciliopathy genes, are also highlighted in this study.
A Neanderthal OAS1 isoform Protects Against COVID-19 Susceptibility and Severity: Results from Mendelian Randomization and Case-Control Studies
Authors: Zhou Sirui , Butler-Laporte Guillaume , Nakanishi Tomoko , Morrison David , Afilalo Jonathan , Afilalo Marc , Laurent Laetitia , Pietzner Maik , Kerrison Nicola , Zhao Kaiqiong , Brunet-Ratnasingham Elsa , Henry Danielle , Kimchi Nofar , Afrasiabi Zaman , Rezk Nardin , Bouab Meriem , Petitjean Louis , Guzman Charlotte , Xue Xiaoqing , Tselios Chris , Vulesevic Branka , Adeleye Olumide , Abdullah Tala , Almamlouk Noor , Chen Yiheng , Chassé Michaël , Durand Madeleine , Pollak Michael , Paterson Clare , Zeberg Hugo , Normark Johan , Frithiof Robert , Lipcsey Miklós , Hultström Michael , Greenwood Celia M T , Langenberg Claudia , Thysell Elin , Mooser Vincent , Forgetta Vincenzo , Kaufmann Daniel E. , Richards J Brent
Published: October 2020

Proteins detectable in peripheral blood may influence COVID-19 susceptibility or severity. However, understanding which circulating proteins are etiologically involved is difficult because their levels may be influenced by COVID-19 itself and are also subject to confounding factors. To identify circulating proteins influencing COVID-19 susceptibility and severity we undertook a large-scale two-sample Mendelian randomization (MR) study, since this study design can rapidly scan hundreds of circulating proteins and reduces bias due to reverse causation and confounding. We identified genetic determinants of 931 circulating proteins in 28,461 SARS-CoV-2 uninfected individuals, retaining only single nucleotide polymorphism near the gene encoding the circulating protein. We found that a standard deviation increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (N = 4,336 cases / 623,902 controls; OR = 0.54, P = 7×10−8), COVID-19 hospitalization (N = 6,406 / 902,088; OR = 0.61, P = 8×10−8) and COVID-19 susceptibility (N = 14,134 / 1,284,876; OR = 0.78, P = 8×10−6). Results were consistent in multiple sensitivity analyses. We then measured OAS1 levels in 504 patients with repeated plasma samples (N=1039) with different COVID-19 outcomes and found that increased OAS1 levels in a non-infectious state were associated with protection against very severe COVID-19, hospitalization and susceptibility. Further analyses suggested that a Neanderthal isoform of OAS1 affords this protection. Thus, evidence from MR and a case-control study supported a protective role for OAS1 in COVID-19 outcomes. Available medicines, such as phosphodiesterase-12 inhibitors, increase OAS1 and could be explored for their effect on COVID-19 susceptibility and severity.
Pilot production of SARS-CoV-2 related proteins in plants: a proof of concept for rapid repurposing of indoors farms into biomanufacturing facilities
Authors: Diego-Martin Borja , González Beatriz , Vazquez-Vilar Marta , Selma Sara , Mateos-Fernández Rubén , Gianoglio Silvia , Fernández-del-Carmen Asun , Orzáez Diego
Published: October 2020

The current CoVid-19 crisis is revealing the strengths and the weaknesses of the world’s capacity to respond to a global health crisis. A critical weakness has resulted from the excessive centralization of the current biomanufacturing capacities, a matter of great concern, if not a source of nationalistic tensions. On the positive side, scientific data and information have been shared at an unprecedented speed fuelled by the preprint phenomena, and this has considerably strengthened our ability to develop new technology-based solutions. In this work we explore how, in a context of rapid exchange of scientific information, plant biofactories can serve as a rapid and easily adaptable solution for local manufacturing of bioreagents, more specifically recombinant antibodies. For this purpose, we tested our ability to produce, in the framework of an academic lab and in a matter of weeks, milligram amounts of six different recombinant monoclonal antibodies against SARS-CoV-2 inNicotiana benthamiana.For the design of the antibodies we took advantage, among other data sources, of the DNA sequence information made rapidly available by other groups in preprint publications. mAbs were all engineered as single-chain fragments fused to a human gamma Fc and transiently expressed using a viral vector. In parallel, we also produced the recombinant SARS-CoV-2 N protein and its Receptor Binding Domain (RBD)in plantaand used them to test the binding specificity of the recombinant mAbs. Finally, for two of the antibodies we assayed a simple scale-up production protocol based on the extraction of apoplastic fluid. Our results indicate that gram amounts of anti-SARS-CoV-2 antibodies could be easily produced in little more than 6 weeks in repurposed greenhouses with little infrastructure requirements usingN. benthamianaas production platform. Similar procedures could be easily deployed to produce diagnostic reagents and, eventually, could be adapted for rapid therapeutic responses.
Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19
Authors: Clark Jordan J. , Penrice-Randal Rebekah , Sharma Parul , Kipar Anja , Dong Xiaofeng , Pennington Shaun H. , Marriott Amy E. , Colombo Stefano , Davidson Andrew , Williamson Maia Kavanagh , Matthews David A. , Turtle Lance , Prince Tessa , Hughes Grant L. , Patterson Edward I. , Shawli Ghada , Mega Daniele F. , Subramaniam Krishanthi , Sharp Jo , McLaughlin Lynn , Zhou En-Min , Turner Joseph D. , Biagini Giancarlo , Owen Andrew , Hiscox Julian A. , Stewart James P.
Published: October 2020

COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2, a recently emerged coronavirus that rapidly caused a pandemic. Coalescence of this virus with seasonal respiratory viruses, particularly influenza virus is a global health concern. To investigate this, transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) were first infected with IAV followed by SARS-CoV-2. The host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 only. Infection of mice with each individual virus resulted in a disease phenotype compared to control mice. Although SARS-CoV-2 RNA synthesis appeared significantly reduced in the sequentially infected mice, they exhibited more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to singly infected or control mice. The sequential infection also exacerbated the extrapulmonary encephalitic manifestations associated with SARS-CoV-2 infection. Conversely, prior infection with a commercially available, multivalent live-attenuated influenza vaccine (Fluenz tetra) elicited the same reduction in SARS-CoV-2 RNA synthesis albeit without the associated increase in disease severity. This suggests that the innate immune response stimulated by infection with IAV is responsible for the observed inhibition of SARS-CoV-2, however, infection with attenuated, apathogenic influenza vaccine does not result in an aberrant immune response and enhanced disease severity. Taken together, the data suggest that the concept of ‘twinfection’ is deleterious and mitigation steps should be instituted as part of a comprehensive public health response to the COVID-19 pandemic.
Evolution of Honey Resistance in Experimental Populations of Bacteria Depends on the Type of Honey, and Has no Major Side Effects for Antibiotic Susceptibility
Authors: Bischofberger Anna M. , Pfrunder Cardozo Katia R. , Baumgartner Michael , Hall Alex R.
Published: October 2020

With rising antibiotic resistance, alternative treatments for communicable diseases are increasingly relevant. One possible alternative for some types of infections is honey, used in wound care since before 2000 BCE and more recently in licensed, medical-grade products. However, it is unclear whether medical application of honey results in the evolution of bacterial honey resistance, and whether this has collateral effects on other bacterial traits such as antibiotic resistance. Here, we used single-step screening assays and serial transfer at increasing concentrations to isolate honey-resistant mutants ofEscherichia coli. We only detected bacteria with consistently increased resistance to the honey they evolved in with two of the four tested honey products, and the observed increases were small (maximum two-fold increase in IC90). Genomic sequencing and experiments with single-gene knockouts showed a key mechanism by which bacteria increased their honey resistance was by mutating genes involved in detoxifying methylglyoxal, which contributes to the antibacterial activity ofLeptospermumhoneys. Crucially, we found no evidence that honey adaptation conferred cross-resistance or collateral sensitivity against nine antibiotics from six different classes. These results reveal constraints on bacterial adaptation to different types of honey, improving our ability to predict downstream consequences of wider honey application in medicine.
Presence and Transmission of Mitochondrial Heteroplasmic Mutations in Human Populations of European and African Ancestry
Authors: Liu Chunyu , Fetterman Jessica L. , Qian Yong , Sun Xianbang , Yan Kaiyu , Blackwell Thomas , Pitsillides Achilleas , Cade Brian E. , Wang Heming , Raffield Laura M. , Lange Leslie A. , Anugu Pramod , Abecasis Goncalo , Cupples L Adrienne , Redline Susan , Correa Adolfo , Vasan Ramachandran S , Wilson James , Ding Jun , Levy Daniel ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Published: October 2020

We investigated the concordance of mitochondrial DNA heteroplasmic mutations (heteroplasmies) in different types of maternal pairs (n=6,745 pairs) of European (EA, n=4,718 pairs) and African (AA, n=2,027 pairs) Americans with whole genome sequences (WGSs). The average concordance rate of heteroplasmies was highest between mother-offspring pairs, followed by sibling-sibling pairs and more distantly related maternal pairs in both EA and AA participants. The allele fractions of concordant heteroplasmies exhibited high correlation (R2=0.8) between paired individuals. Compared to concordant heteroplasmies, discordant ones were more likely to locate in coding regions, be nonsynonymous or nonsynonymous-deleterious (p<0.001). The average number of heteroplasmies per individual (i.e. heteroplasmic burden) was at a similar level until older age (70-80 years old) and increased significantly thereafter (p<0.01). The burden of deleterious heteroplasmies (combined annotation-dependent depletion score≥15), however, was significantly correlated with advancing age (20-44, 45-64, ≥65 years, p-trend=0.01). A genome-wide association analysis of the heteroplasmic burden identified many significant (P<5e-8) common variants (minor allele frequency>0.05) at 11p11.12. Many of the top SNPs act as strong long-range cis regulators of protein tyrosine phosphatase receptor type J. This study provides further evidence that mtDNA heteroplasmies may be inherited or somatic. Somatic heteroplasmic variants increase with advancing age and are more likely to have an adverse impact on mitochondrial function. Further studies are warranted for functional characterization of the deleterious heteroplasmies occurring with advancing age and the association of the 11p11.12 region of the nuclear genome with mtDNA heteroplasmy.
Genetic variation in heat tolerance of the coralPlatygyra daedaleaindicates potential for adaptation to ocean warming
Authors: Elder Holland , Weis Virginia , Montalvo-Proano Jose , Mocellin Veronique J.L , Baird Andrew H. , Meyer Eli , Bay Line K.
Published: October 2020

Climate change induced increases in global ocean temperature represent the greatest threat to the persistence of reef ecosystems and most coral populations are projected to experience temperatures above their current bleaching thresholds annually by 2050. Adaptation to higher temperatures is necessary if corals are to persist in a warming future. While many aspects of heat stress have been well studied, few data are available for predicting the capacity for adaptive cross-generational responses in corals. Consistent sets of heat tolerant genomic markers that reliably predict thermal tolerance have yet to be identified. To address this knowledge gap, we quantified the heritability and genetic variation associated with heat tolerance inPlatygyra daedaleafrom the Great Barrier Reef. We tracked the survival of quantitative genetic crosses of larvae in a heat tolerance selection experiment. We also identified allelic shifts in heat-selected survivors compared with paired, non-selected controls. The narrow-sense heritability of survival under heat stress was 0.66 and a total of 1,069 single nucleotide polymorphisms (SNPs) were associated with different survival probabilities. While 148 SNPs were shared between several experimental crosses, no common SNPs were identified for all crosses suggesting that specific combinations of many markers are responsible for heat tolerance. However, we found two regions that overlap with previously identified loci associated with heat tolerance in Persian Gulf populations ofP. daedaleareinforcing the importance of these markers for heat tolerance. These results illustrate the importance of high heritability and the complexity of the genomic architecture underpinning host heat tolerance. These findings suggest that thisP. daedaleapopulation has the genetic prerequisites for adaptation to increasing temperatures. This study also provides knowledge for the development of high throughput genomic tools to screen for variation within and across populations to enhance adaptation through assisted gene flow and assisted migration.
Selective inhibition of histone deacetylase 1 and 3 improves motor phenotype and alleviates transcriptional dysregulation in Huntington’s disease mice
Authors: Hecklau Katharina , Mueller Susanne , Koch Stefan Paul , Mehkary Mustafa Hussain , Kilic Busra , Harms Christoph , Boehm-Sturm Philipp , Yildirim Ferah
Published: October 2020

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease characterized by a late clinical onset of psychiatric, cognitive, and motor symptoms. Transcriptional dysregulation is an early and central disease mechanism which is accompanied by epigenetic alterations in HD. Previous studies demonstrated that targeting transcriptional changes by inhibition of histone deacetylases (HDACs), especially the class I HDACs, provides therapeutic effects. Yet, their exact mechanisms of action and the features of HD pathology, on which these inhibitors act remain to be elucidated. Here, using transcriptional profiling, we found that selective inhibition of HDAC1 and HDAC3 by RGFP109 repaired the expression of a number of genes, including the transcription factor genesNeurod2andNr4a2, and 43% of the gene sets that were dysregulated by mutant Huntingtin expression in the striatum and improved motor skill learning deficit in the R6/1 mouse model of HD. RGFP109-treated R6/1 mice showed improved coordination on the RotaRod over four consecutive trials, while vehicle-treated R6/1 animals displayed no improvement in coordination skills and fell 50 seconds earlier off the rod in the fourth trial. We also found, by volumetric MRI, a widespread brain atrophy in the R6/1 mice at the symptomatic disease stage, on which RGFP109 showed a modest effect. Collectively, our combined work presents new evidence for specific HDAC1 and HDAC3 inhibition as a therapeutic strategy for alleviating the phenotypic and molecular features of HD.
A Fast Detection Method for Wheat Mould Based on Biophotons
Authors: Yue-hong Gong , Tie-jun Yang , Yi-tao Liang , Hong-yi Ge , Liang Chen
Published: October 2020

Mould is a common phenomenon in stored wheat. First, mould will decrease the quality of wheat kernels. Second, the mycotoxins metabolized by mycetes are very harmful for humans. Therefore, the fast and accurate examination of wheat mould is vitally important to evaluating its storage quality and subsequent processing safety. Existing methods for examining wheat mould mainly rely on chemical methods, which always involve complex and long pretreatment processes, and the auxiliary chemical materials used in these methods may pollute our environment. To improve the determination of wheat mould, this paper proposed a type of green and nondestructive determination method based on biophotons. The specific implementation process is as follows: first, the ultra-weak luminescence between healthy and mouldy wheat samples are measured repeatedly by a biophotonic analyser, and then, the approximate entropy and multiscale approximate entropy are separately introduced as the main classification features. Finally, the classification performances have been tested using the support vector machine(SVM). The ROC curve of the newly established classification model shows that the highest recognition rate can reach 93.6%, which shows that our proposed classification model is feasible and promising for detecting wheat mould.
Roles of signaling compounds and WRKY31 in the defense ofPinus massonianaL. againstDendrolimus punctatus
Authors: Chen Hu , Hu Ying , Liang Xingxing , Xie Junkang , Xu Huilan , Luo Qunfeng , Yang Zhangqi
Published: October 2020

Dendrolimus punctatusis an important pest affecting Masson pine (Pinus massonianaL.) forests and can cause serious economic and ecological losses. WRKY transcription factors play important roles in coping with various environmental stresses. In particular, recent studies have shown that WRKY transcription factors play an important role in plant responses against herbivorous insects. However, the mechanisms underlying the actions of these genes in the defense responses ofP. massonianaL. are still unclear. Our previous study provided evidence that WRKY may play an important role in the insect resistance ofP. massonianaL. In this study, application of semiochemicals such as exogenous hormones and Ca2+by spraying increased the concentrations of endogenous hormones, terpenoid synthases, and volatile substances inP. massonianaL. and effectively improved its resistance toD. punctatus. After analyzing the WRKY family ofP. massonianaL., the PmWRKY31 gene was selected and studied. Yeast two-hybrid assays showed that the LP8 gene interacted with PmWRKY31. Fluorescence-based quantitative polymerase chain reaction showed that after treatment with exogenous hormones and Ca2+, the expression levels of the PmWRKY31 gene, hormonal signal–related genes, and terpene biosynthetic pathway–related genes were significantly increased, whereas the expression of the LP8 gene was decreased. Therefore, the PmWRKY31 and LP8 genes affected downstream gene expression by positively and negatively regulating the hormone signaling pathways, respectively. This result provides theoretical support for the involvement of WRKY transcription factors in the insect resistance ofP. massonianaL. through their regulation of hormone signaling.
Elucidating the viral and host factors enabling the cross-species transmission of primate lentiviruses from simians to humans
Authors: Tebit Denis M. , Nickel Gabrielle , Gibson Richard , Carpenter Crystal , Rodriguez Myriam , Hathaway Nicolas J. , Bain Katie , Reyes-Rodriguez Angel L. , Bonogo Jennifer , Canaday David , McDonald David , Bailey Jeffrey A. , Arts Eric J.
Published: October 2020

The HIV-1 epidemic originated from a cross-species transmission of a primate lentivirus from chimpanzees to humans near the turn of the 18thcentury. Simian immunodeficiency viruses have been jumping between old world monkeys in West/Central Africa for thousands of years. So why did HIV-1 only emerge in the past century? This study examined the replicative fitness, transmission, restriction, and cytopathogenicity of 26 primate lentiviruses. Pairwise competitions of these primate lentiviruses revealed that SIVcpz had the highest replicative fitness in human or chimpanzee peripheral blood mononuclear cells, even higher fitness than HIV-1 group M strains responsible for 37 million infections worldwide. In contrast the “HIV-2 lineage” (SIVsmm, SIVmac, SIVagm, and HIV-2) had the lowest replicative fitness. SIVcpz strains were less inhibited by human restriction factors than the “HIV-2 lineage” strains, a restriction that was inversely correlated with replicative fitness. SIVcpz from the chimpanzee subspeciesPan troglodytes troglodytes(Ptt) was slightly more fit in human cells than the strains fromPt schweinfurthii(Pts). However, unlike all other primate lentiviruses (including the HIV-2 lineage), SIVcpz was nonpathogenic in human tonsillar tissue and did not deplete CD4+ T-cells, consistent with the slow or nonpathogenic disease observed in chimpanzees. Despite the close phylogenetic relationship between SIVcpz_Ptt and HIV-1, this epidemic was either caused by cross species transmission of a rare, undiscovered SIVcpz strain of higher virulence or higher virulence differentially evolved among HIV-1 subtypes during the human epidemic.

Author summary

Invasion of wild animal habitats by humans can have devastating consequences for the human population as evident by the HIV-1 and SARS-CoV-2 epidemics. With SARS-CoV-2, a recent zoonotic jump, likely from bats, will help to identify a coronavirus progenitor. In contrast, simian immunodeficiency virus (SIV) jumped into humans over 100 years ago from a possibly extinct sub-species of chimpanzees and/or extinct lineage of SIV. We examined replicative fitness and pathogenesis of 26 different primate lentiviruses in human and chimpanzee primary lymphoid cells from blood and within tonsils. SIV from a specific chimpanzee species and lowland gorillas were the most capable of infecting and replicating in human and chimp lymphoid cells but they did not result in the pathogenesis related to disease in humans. In contrast, SIV from other old world monkeys were pathogenic but could not replicate efficiently in human cells. We propose the main HIV-1 is derived from a distinct jump of a very rare SIV strain in chimps leading to AIDS pandemic.
The proficiency of the original host species determines community-level plasmid dynamics
Authors: Kottara Anastasia , Hall James P.J. , Brockhurst Michael A.
Published: October 2020

Plasmids are common in natural bacterial communities, facilitating bacterial evolution via horizontal gene transfer. Bacterial species vary in their proficiency to host plasmids: Whereas plasmids are stably maintained in some species regardless of selection for plasmid-encoded genes, in other species, even beneficial plasmids are rapidly lost. It is, however, unclear how this variation in host proficiency affects plasmid persistence in communities. Here, we test this using multispecies bacterial soil communities comprising species varying in their proficiency to host a large conjugative mercury resistance plasmid. Plasmids reached higher community-level abundance where beneficial and when introduced to the community in a more proficient host species. Proficient plasmid host species were also better able to disseminate the plasmid to a wider diversity of host species. These findings suggest that the dynamics of plasmids in natural bacterial communities depend not only upon the plasmid’s attributes and the selective environment, but also upon the proficiency of their host species.
Degradation of SARS-CoV-2 receptor ACE2 by tobacco carcinogen-induced Skp2 in lung epithelial cells
Authors: Wang Gui-Zhen , Zhao Qun , Liang Fan , Zhang Chen , Zhang Hui , Wang Jun , Chen Zhen-Yin , Wu Ran , Yu Hong , Sun Bei-Bei , Guo Hua , Feng Ruie , Xu Kai-Feng , Zhou Guang-Biao
Published: October 2020

An unexpected observation among the COVID-19 pandemic is that smokers constituted only 1.4-18.5% of hospitalized adults, calling for an urgent investigation to determine the role of smoking in SARS-CoV-2 infection. Here, we show that cigarette smoke extract (CSE) and carcinogen benzo(a)pyrene (BaP) increaseACE2mRNA but trigger ACE2 protein catabolism. BaP induces an aryl hydrocarbon receptor (AhR)-dependent upregulation of the ubiquitin E3 ligase Skp2 for ACE2 ubiquitination. ACE2 in lung tissues of non-smokers is higher than in smokers, consistent with the findings that tobacco carcinogens downregulate ACE2 in mice. Tobacco carcinogens inhibit SARS-CoV-2 Spike protein pseudovirions infection of the cells. Given that tobacco smoke accounts for 8 million deaths including 2.1 million cancer deaths annually and Skp2 is an oncoprotein, tobacco use should not be recommended and cessation plan should be prepared for smokers in COVID-19 pandemic.
Carbon dots deposition in adult bones reveal areas of growth, injury and regeneration
Authors: DuMez Rachel , Miyanji Esmail H. , Corado-Santiago Lesly , Barrameda Bryle , Zhou Yiqun , Hettiarachchi Sajini D. , Leblanc Roger M. , Skromne Isaac
Published: October 2020

C-dots synthesized from carbon nanopowder (oxidation, hydrothermal) are particularly attractive theragnostic agents for bone-related injuries and disease due to their bright fluorescence and high binding affinity and specificity for bones, as demonstrated in a larval animal model. Larval bone development, however, is significantly different from the bone growth, repair and regeneration processes occurring in adults. Using adult zebrafish, we investigated C-dots’ interactions with adult skeletal structures. Upon injection, C-dots were observed at the surface of bones, at sites of appositional growth. In regenerating bones, C-dots were observed at the core and on the surface of the bones depending on the age of the tissue. C-dot’s deposition occurred within 30 min of delivery and it was highly selective. Importantly, their deposition did not interfere with bone regeneration or the animal’s health. Together, these properties establish C-dots as novel tools for the diagnostic and treatment of adult bone-related injuries and diseases.
Distinct progenitor behavior underlying neocortical gliogenesis related to tumorigenesis
Authors: Shen Zhongfu , Lin Yang , Yang Jiajun , Jörg David J. , Peng Yuwei , Zhang Xiuli , Xu Yifan , Hernandez Luisirene , Ma Jian , Simons Benjamin D. , Shi Song-Hai
Published: October 2020

Radial glial progenitors (RGPs) are responsible for producing the vast majority of neurons and glia in the neocortex. While RGP behavior and progressive generation of neocortical neurons have been delineated, the exact process of neocortical gliogenesis remains elusive. Here, we report the precise progenitor cell behavior and gliogenesis program at single-cell resolution in the mouse neocortex. RGPs transition from neurogenesis to gliogenesis progressively, producing astrocytes, oligodendrocytes, or both in well-defined propensities of 60%:15%:25%, respectively, via fate-restricted “intermediate” precursor cells. While the total number of precursor cells generated by individual RGPs appears stochastic, the output of individual precursor cells exhibit clear patterns in number and subtype, and form discrete local subclusters. Clonal loss of tumor suppressor Neurofibromatosis type 1 leads to excessive production of glia selectively, especially oligodendrocyte precursor cells. These results delineate the cellular program of neocortical gliogenesis quantitatively and suggest the cellular and lineage origin of primary brain tumor.
Holistic face recognition is an emergent phenomenon of spatial integration in face-selective regions
Authors: Poltoratski Sonia , Kay Kendrick , Finzi Dawn , Grill-Spector Kalanit
Published: October 2020

Spatial processing by receptive fields is a core property of the visual system. However, it is unknown how spatial coding in high-level regions contributes to recognition behavior. As face inversion is thought to disrupt typical ‘holistic’ processing of information in faces, we mapped population receptive fields (pRFs) with upright and inverted faces in the human visual system. In face-selective regions, but not primary visual cortex, pRFs and overall visual field coverage were smaller and shifted downward in response to face inversion. From these measurements, we successfully predicted the relative behavioral detriment of face inversion at different positions in the visual field. This correspondence between neural measurements and behavior demonstrates how spatial integration in face-selective regions enables holistic processing. These results not only show that spatial processing in high-level visual regions is dynamically used towards recognition, but also suggest a powerful approach for bridging neural computations by receptive fields to behavior.
Anticipation of temporally structured events in the brain
Authors: Lee Caroline S. , Aly Mariam , Baldassano Christopher
Published: October 2020

1

Learning about temporal structure is adaptive because it enables the generation of expectations. We examined how the brain uses experience in structured environments to anticipate upcoming events. During fMRI, individuals watched a 90-second movie clip six times. Using a Hidden Markov Model applied to searchlights across the whole brain, we identified temporal shifts between activity patterns evoked by the first vs. repeated viewings of the movie clip. In many regions throughout the cortex, neural activity patterns for repeated viewings shifted to precede those of initial viewing by up to 15 seconds. This anticipation varied hierarchically in a posterior (less anticipation) to anterior (more anticipation) fashion. We also identified specific regions in which the timing of the brain’s event boundaries were related to those of human-labeled event boundaries, with the timing of this relationship shifting on repeated viewings. With repeated viewing, the brain’s event boundaries came to precede human-annotated boundaries by 1-4 seconds on average. Together, these results demonstrate a hierarchy of anticipatory signals in the human brain and link them to subjective experiences of events.
Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons
Authors: Steg Leonard C. , Shireby Gemma L. , Imm Jennifer , Davies Jonathan P. , Franklin Alice , Flynn Robert , Namboori Seema C. , Bhinge Akshay , Jeffries Aaron R. , Burrage Joe , Neilson Grant W. A. , Walker Emma M. , Perfect Leo W. , Price Jack , McAlonan Grainne , Srivastava Deepak P. , Bray Nicholas J. , Cope Emma L. , Jones Kimberly M. , Allen Nicholas D. , Pishva Ehsan , Dempster Emma L. , Lunnon Katie , Mill Jonathan , Hannon Eilis
Published: October 2020

Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and iPSC-derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases.
Widespread intron retention impairs protein homeostasis in C9orf72 ALS brains
Authors: Wang Qingqing , Conlon Erin G. , Manley James L. , Rio Donald C.
Published: October 2020

The GGGGCC hexanucleotide expansion in C9orf72 (C9) is the most frequent known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet a clear understanding of how C9 fits into the broader context of ALS/FTD pathology has remained lacking. The repetitive RNA derived from the C9 repeat is known to sequester hnRNPH, a splicing regulator, into insoluble aggregates, resulting in aberrant alternative splicing. Furthermore, hnRNPH insolubility and altered splicing of a robust set of targets have been observed to correlate in C9 and sporadic ALS/FTD patients alike, suggesting that changes along this axis are a core feature of disease pathogenesis. Here, we characterize previously uncategorized RNA splicing defects involving widespread intron retention affecting almost 2000 transcripts in C9ALS/FTD brains exhibiting a high amount of sequestered, insoluble hnRNPH. These intron retention events appear not to alter overall expression levels of the affected transcripts but rather the protein-coding regions. These retained introns affect transcripts in multiple cellular pathways predicted to be involved in C9 as well as sporadic ALS/FTD etiology, including the proteasomal and autophagy systems. The retained intron pre-mRNAs display a number of characteristics, including enrichment of hnRNPH-bound splicing enhancer motifs and a propensity for G-quadruplex (G-Q) formation, linking the defective splicing directly to high amounts of sequestered hnRNPH. Together, our results reveal previously undetected splicing defects in high insoluble hnRNPH-associated C9ALS brains, suggesting a feedback between effective RNA-binding protein dosage and protein quality control in C9, and perhaps all, ALS/FTD.
A new approach of surfaces registration considering form errors for precise assembly
Authors: Zhang Qiushuang , Jin Xin , Liu Zhihua , Zhang Zhijing , Fang Yan , Zhang Zhongqing , Ledoux Yann
Published: October 2020

Purpose

The modern manufacturing industry has put forward higher requirements for the assembly accuracy of components with the development of the industrial technology. For precision assembly, the traditional assembly process study based on tolerance has had difficulty in meeting these requirements. Hence, the distribution of the form errors must be considered. The registration between the two mating surfaces with form errors determines the parts’ assembly position, and is the basis for the prediction and control of the assembly accuracy. This study aims to provide a new surfaces registration method which takes form errors into consideration.

Design/methodology/approach

This study presents a new registration approach based on the minimum potential energy. A unique set of contact points on mating surfaces that meet the actual conditions can be obtained and the spatial position of the assembled part is calculated.

Findings

The experimental results show that the calculated values are in good agreement with the experimental values. Furthermore, the root mean square error is within 2%, which proves the validity and accuracy of the approach.

Originality/value

This paper provides an effective and new method for precision assembly which takes form errors into consideration. The method can give the optimal solution of the contact points, which is more consistent with the actual assembly situation and provides a basis for predicting assembly accuracy.
Assembly kits with variable part physical attributes: warehouse layout design and assignment procedure
Authors: Bortolini Marco , Faccio Maurizio , Gamberi Mauro , Pilati Francesco
Published: October 2020

Purpose

The kitting feeding policy creates kits with the parts of each product to assemble. Each kit contains elements with heterogeneous physical properties imposing heterogeneous logistic facilities and management solutions for storage and handling. The purpose of this paper is to present and apply a two-step procedure to design the part warehouse layout and to assign locations in case of kitting with high-variety part attributes. The proposed procedure aims at reducing the kitting travelled distance, shortening the picker paths, best positioning the components in the warehouse to enhance the possibility of creating kits through a single corridor access. The saturation of the warehouse and the minimization of the required storage space are also considered.

Design/methodology/approach

Starting from part categorization, the proposed two-step procedure, of general applicability, designs the component warehouse, sizing the corridors (Step 1) before clustering the kits in terms of part commonality and best-assigning clusters to corridors (Step 2) with the goal of reducing the travelled distance and saturating the available storage space.

Findings

A comparison model considers the traditional versus the proposed warehouse layout highlighting the potential saving in the picker travelled distance. A case study taken from the harvesting machine agricultural sector exemplifies the applicability and the practical implications of this research.

Originality/value

Elements of originality are the warehouse design strategy and the assignment model for parts based on their physical attributes and their occurrence in the assembly kits. Finally, the case study taken from industry, with a high number of components and part categories, adds value to the research making the proposed procedure able to address large-scale industrial problems.
In-space structural assembly using predefined performance based method
Authors: Zhang Xianliang , Zhu Weibing , Wu Xiande , Song Ting , Xie Yaen , Zhao Han
Published: October 2020

Purpose

The purpose of this paper is to propose a pre-defined performance robust control method for pre-assembly configuration establishment of in-space assembly missions, and collision avoidance is considered during the configuration establishment process.

Design/methodology/approach

First, six-degrees-of-freedom error kinematic and dynamic models of relative translational and rotational motion between transportation systems are developed. Second, the prescribed transient-state performance bounds of tracking errors are designed. In addition, based on the backstepping, combining the pre-defined performance control method with a robust control method, a pre-defined performance robust controller is designed.

Findings

By designing prescribed transient-state performance bounds of tracking errors to guarantee that there is no overshoot, collision-avoidance can be achieved. Combining the pre-defined performance control method with a robust control method, robustness to disturbance is guaranteed.

Originality/value

This paper proposed a pre-defined performance robust control method. Simulation results demonstrate that the proposed controller can achieve a pre-assembly configuration establishment with collision avoidance in the existence of external disturbances.
Rethinking dominant theories used in information systems field in the digital platform era
Authors: Hanafizadeh Payam , Khosravi Bayan , Tabatabaeian Seyed Habibollah
Published: October 2020

Purpose

Selecting an appropriate theory has always remained a critical task for the digital policy researchers. The literature seems to miss providing theoretical accounts of policy view of the digital platforms governance and offering tools for measuring the effectiveness of policies. To this end, this paper aims to provide a critical review and comparison of dominant information systems (IS) theories used. It highlights the weaknesses of these theories to explain technology features and actor- technology interactions with the rising trend of digital platforms. The main argument of this research is that the policymakers will not have adequate tools for policymaking of digital platforms by following the assumptions of theories used dominantly in the IS field.

Design/methodology/approach

This paper analyzes the assumptions of dominant IS theories and their applications in the digital policy literature. Then, it shows to what extent these theories are incapable of conceptualizing features of technology and actors’ role in policymaking and governance of digital platforms.

Findings

This paper identifies three aspects of digital platforms, including layered architecture, multisided (“side” means “participants”) and user interaction based, that dominant IS theories have shortcomings in explaining them.

Practical implications

The findings of this research can help authorities to take a more realistic view in defining digital platform policy objectives and applying more appropriate tools in policy implementation.

Originality/value

Discussing insights into the shortcomings of theories helps to define the theoretical requirements for studying policymaking and governance of digital platforms. It also suggests opportunities and recommendations for future studies.
Exploring multiple diversification strategies for academic citation contexts recommendation
Authors: Chen Haihua , Yang Yunhan , Lu Wei , Chen Jiangping
Published: October 2020

Purpose

Citation contexts have been found useful in many scenarios. However, existing context-based recommendations ignored the importance of diversity in reducing the redundant issues and thus cannot cover the broad range of user interests. To address this gap, the paper aims to propose a novelty task that can recommend a set of diverse citation contexts extracted from a list of citing articles. This will assist users in understanding how other scholars have cited an article and deciding which articles they should cite in their own writing.

Design/methodology/approach

This research combines three semantic distance algorithms and three diversification re-ranking algorithms for the diversifying recommendation based on the CiteSeerXdata set and then evaluates the generated citation context lists by applying a user case study on 30 articles.

Findings

Results show that a diversification strategy that combined “word2vec” and “Integer Linear Programming” leads to better reading experience for participants than other diversification strategies, such as CiteSeerXusing a list sorted by citation counts.

Practical implications

This diversifying recommendation task is valuable for developing better systems in information retrieval, automatic academic recommendations and summarization.

Originality/value

The originality of the research lies in the proposal of a novelty task that can recommend a diversification context list describing how other scholars cited an article, thereby making citing decisions easier. A novel mixed approach is explored to generate the most efficient diversifying strategy. Besides, rather than traditional information retrieval evaluation, a user evaluation framework is introduced to reflect user information needs more objectively.