bluuebunny/crossref_metadata_2025 huggingface dataset:
Digital contact tracing contributes little to COVID-19 outbreak containment
Authors: Burdinski A. , Brockmann D. , Maier B. F.
Published: June 2021

Digital contact tracing applications have been introduced in many countries to aid in the containment of COVID-19 outbreaks. Initially, enthusiasm was high regarding their implementation as a non-pharmaceutical intervention (NPI). Yet, no country was able to prevent larger outbreaks without falling back to harsher NPIs, and the total effect of digital contact tracing remains elusive. Based on the results of empirical studies and modeling efforts, we show that digital contact tracing apps might have prevented cases on the order of single-digit percentages up until now, at best. We show that this poor impact can be attributed to a combination of low participation rates, a non-flexible reliance on symptom-based testing, low engagement of participants, and delays between testing and test result upload. We find that contact tracing does not change the epidemic threshold and exclusively prevents more cases during the supercritical phase of an epidemic, making it unfit as a tool to prevent outbreaks. Locally clustered contact structures may increase the intervention’s efficacy, but only if the number of contacts per individual is homogeneously distributed, a condition usually not found in contact networks. Our results suggest that policy makers cannot rely on digital contact tracing to contain outbreaks of COVID-19 or similar diseases.
Predicting age from 100,000 one week-long 100Hz wrist accelerometer records of physical activity
Authors: Le Goallec Alan , Collin Sasha , Jabri M’Hamed , Diai Samuel , Vincent Théo , Patel Chirag J.
Published: June 2021

Physical activity improves quality of life, physical health and mental health, and is also an important protective factor against highly prevalent age-related diseases such as cardiovascular diseases, diabetes, cancer and mental health. With age, physical activity tends to decrease, leading down a vicious cycle that increases vulnerability to disease in the elderly. In the following, we trained neural network architectures to predict age from 115,456 one week-long 100Hz wrist accelerometer recordings from the UK Biobank (R-Squared=63.5±2.4%; root mean squared error=4.7±0.1 years). We achieved this performance by preprocessing the raw data as 2,271 scalar features, 113 time series and four images. We also considered the raw signal at different time scales (weekly activity patterns vs. gait). We then defined accelerated aging for a participant as being predicted older than one’s actual age and aimed to characterize these participants. We performed a genome wide association on the accelerated aging phenotypes to estimate its heritability (h_g2=12.3±0.9%) and identified nine single nucleotide polymorphisms in seven genes associated with it (e.g HIST1H4L, involved in chromatin organization). Similarly, we identified biomarkers (e.g blood pressure), clinical phenotypes (e.g chest pain), diseases (e.g hypertension), environmental (e.g smoking) and socioeconomic (e.g income and education) variables associated with accelerated aging. We conclude that physical activity-derived biological age is a complex phenotype with both genetic and non-genetic factors.
Population disruption: estimating changes in population distribution of the UK during the COVID-19 pandemic
Authors: Gibbs Hamish , Waterlow Naomi R , Cheshire James , Danon Leon , Liu Yang , Grundy Chris , Kucharski Adam J. ,   LSHTM CMMID COVID-19 Working Group, Eggo Rosalind M.
Published: June 2021

Mobility data have demonstrated major changes in human movement patterns in response to COVID-19 and associated interventions in many countries. This can involve sub-national redistribution, short-term relocations as well as international migration. In this paper, we combine detailed location data from Facebook measuring the location of approximately 6 million daily active Facebook users in 5km2 tiles in the UK with census-derived population estimates to measure population mobility and redistribution. We provide time-varying population estimates and assess spatial population changes with respect to population density and four key reference dates in 2020 (First lockdown, End of term, Beginning of term, Christmas). We also show how population estimates derived from the distribution of Facebook users vary compared to mid-2020 small area population estimates by the UK national statistics agencies. We estimate that between March 2020 and March 2021, the total population of the UK declined and we identify important spatial variations in this population change, showing that low-density areas have experienced lower population decreases than urban areas. We estimate that, for the top 10% highest population tiles, the population has decreased by 6.6%. Further, we provide evidence that geographic redistributions of population within the UK coincide with dates of non-pharmaceutical interventions including lockdowns and movement restrictions, as well as seasonal patterns of migration around holiday dates. The methods used in this study reveal significant changes in population distribution at high spatial and temporal resolutions that have not previously been quantified by available demographic surveys in the UK. We found early indicators of potential longer-term changes in the population distribution of the UK although it is not clear if these changes may persist after the COVID-19 pandemic.
Diversity ofTreponema denticolaand other oral treponeme lineages in subjects with periodontitis and gingivitis
Authors: Zeng Huihui , Chan Yuki , Gao Wenling , Leung W. Keung , Watt Rory M.
Published: June 2021

More than 75 species/species-level phylotypes of taxa belonging to the genusTreponemainhabit the human oral cavity.Treponema denticolais commonly associated with periodontal disease, but the etiological roles and ecological distributions of other oral treponemes remain more obscure. Here, we compared the clinical distributions of phylogroup 1 and 2 oral treponemes in subgingival plaque sampled from Chinese subjects with periodontitis (n=10) and gingivitis (n=8), via the sequence analysis of the highly-conservedpyrH‘housekeeping’ gene. Two PCR primer sets that respectively targeted oral phylogroup 1 and 2 treponemepyrHgenes were used to construct plasmid clone-amplicon libraries for each subject, which were sequenced for bioinformatic analysis. 1,204 quality-filtered, full-lengthpyrHgene sequences were obtained from the cohort (median: 61.5; range: 59-83 of clonedpyrHsequences per subject), which were assigned to 34 ‘pyrHgenotypes’ (pyrH001-pyrH034; 97% sequence-identity cut-off). 18pyrHgenotypes (536pyrHsequences) corresponded to phylogroup 1 treponeme taxa (includingTreponema vincentii, Treponema medium). 16 pyrH genotypes (668pyrHsequences) corresponded toT. denticolaand other phylogroup 2 treponemes. Periodontitis subjects contained a greater diversity of phylogroup 2pyrHgenotypes, compared to gingivitis subjects (Mann-Whitney U-test). OneT. denticola pyrHgenotype (pyrH001) was highly prevalent: detected in 10/10 periodontitis and 6/8 gingivitis subjects. Several subjects harboured multipleT. denticola pyrHgenotypes. Non-metric multidimensional scaling and PERMANOVA tests revealed no significant differences in overallpyrHgenotype compositions between periodontitis and gingivitis subjects. In conclusion, our results clearly show that subjects with periodontitis and gingivitis commonly harbour highly-diverse oral treponeme communities.
Drug repurposing based on a Quantum-Inspired method versus classical fingerprinting uncovers potential antivirals against SARS-CoV-2 including vitamin B12
Authors: Jimenez-Guardeño Jose M. , Ortega-Prieto Ana Maria , Moreno Borja Menendez , Maguire Thomas J.A. , Richardson Adam , Diaz-Hernandez Juan Ignacio , Perez Javier Diez , Zuckerman Mark , Playa Albert Mercadal , Deline Carlos Cordero , Malim Michael H. , Martinez-Nunez Rocio T
Published: June 2021

The COVID-19 pandemic has accelerated the need to identify new therapeutics at pace, including through drug repurposing. We employed a Quadratic Unbounded Binary Optimization (QUBO) model, to search for compounds similar to Remdesivir (RDV), the only antiviral against SARS-CoV-2 currently approved for human use, using a quantum-inspired device. We modelled RDV and compounds present in the DrugBank database as graphs, established the optimal parameters in our algorithm and resolved the Maximum Weighted Independent Set problem within the conflict graph generated. We also employed a traditional Tanimoto fingerprint model. The two methods yielded different lists of compounds, with some overlap. While GS-6620 was the top compound predicted by both models, the QUBO model predicted BMS-986094 as second best. The Tanimoto model predicted different forms of cobalamin, also known as vitamin B12. We then determined the half maximal inhibitory concentration (IC50) values in cell culture models of SARS-CoV-2 infection and assessed cytotoxicity. Lastly, we demonstrated efficacy against several variants including SARS-CoV-2 Strain England 2 (England 02/2020/407073), B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). Our data reveal that BMS-986094 and different forms of vitamin B12 are effective at inhibiting replication of all these variants of SARS-CoV-2. While BMS-986094 can cause secondary effects in humans as established by phase II trials, these findings suggest that vitamin B12 deserves consideration as a SARS-CoV-2 antiviral, particularly given its extended use and lack of toxicity in humans, and its availability and affordability. Our screening method can be employed in future searches for novel pharmacologic inhibitors, thus providing an approach for accelerating drug deployment.
Intrinsic and extrinsic regulation of human fetal bone marrow haematopoiesis and perturbations in Down syndrome
Authors: Jardine Laura , Webb Simone , Goh Issac , Londoño Mariana Quiroga , Reynolds Gary , Mather Michael , Olabi Bayanne , Stephenson Emily , Botting Rachel A. , Horsfall Dave , Engelbert Justin , Maunder Daniel , Mende Nicole , Murnane Caitlin , Dann Emma , McGrath Jim , King Hamish , Kucinski Iwo , Queen Rachel , Carey Christopher D , Shrubsole Caroline , Poyner Elizabeth , Acres Meghan , Jones Claire , Ness Thomas , Coulthard Rowan , Elliott Natalina , O’Byrne Sorcha , Haltalli Myriam L. R. , Lawrence John E , Lisgo Steven , Balogh Petra , Meyer Kerstin B , Prigmore Elena , Ambridge Kirsty , Jain Mika Sarkin , Efremova Mirjana , Pickard Keir , Creasey Thomas , Bacardit Jaume , Henderson Deborah , Coxhead Jonathan , Filby Andrew , Hussain Rafiqul , Dixon David , McDonald David , Popescu Dorin-Mirel , Kowalczyk Monika S. , Li Bo , Ashenberg Orr , Tabaka Marcin , Dionne Danielle , Tickle Timothy L. , Slyper Michal , Rozenblatt-Rosen Orit , Regev Aviv , Behjati Sam , Laurenti Elisa , Wilson Nicola K. , Roy Anindita , Göttgens Berthold , Roberts Irene , Teichmann Sarah A. , Haniffa Muzlifah
Published: June 2021

Throughout postnatal life, haematopoiesis in the bone marrow (BM) maintains blood and immune cell production. Haematopoiesis first emerges in human BM at 12 post conception weeks while fetal liver (FL) haematopoiesis is still expanding. Yet, almost nothing is known about how fetal BM evolves to meet the highly specialised needs of the fetus and newborn infant. Here, we detail the development of fetal BM including stroma using single cell RNA-sequencing. We find that the full blood and immune cell repertoire is established in fetal BM in a short time window of 6-7 weeks early in the second trimester. Fetal BM promotes rapid and extensive diversification of myeloid cells, with granulocytes, eosinophils and dendritic cell (DC) subsets emerging for the first time. B-lymphocyte expansion occurs, in contrast with erythroid predominance in FL at the same gestational age. We identify transcriptional and functional differences that underlie tissue-specific identity and cellular diversification in fetal BM and FL. Finally, we reveal selective disruption of B-lymphocyte, erythroid and myeloid development due to cell intrinsic differentiation bias as well as extrinsic regulation through an altered microenvironment in the fetal BM from constitutional chromosome anomaly Down syndrome during this crucial developmental time window.
RNAseq analysis reveals dynamic metaboloepigenetic profiles of human, mouse and bovine pre-implantation embryos
Authors: Milazzotto Marcella Pecora , Noonan Michael James , de Almeida Monteiro Melo Ferraz Marcia
Published: June 2021

Metaboloepigenetic regulation (metabolites regulating the cellular epigenome inducing long-term changes), has been reported in stem cells, germ cells and tumor cells. Embryonic metaboloepigenetics, however, have just begun to be described. Here we analyzed RNAseq data to characterize the metaboloepigenetic profiles of human, mouse and bovine pre-implantation embryos. In embryos, metaboloepigenetic reprogramming is species specific, varies with the developmental stage and is disrupted with in vitro culture. Although the idea that the in vitro environment may influence embryo development is not new, there has been little progress on improving pregnancy rates after more than 43 years using in vitro fertilization. Hence, the present data on embryonic metaboloepigenetic will contribute to understanding how the in vitro manipulation affects the metaboloepigenetic status of early embryos, which can be used to establish culture strategies aimed at improving the in vitro environment and, consequently, pregnancy rates and offspring health.
Patterns of and processes shaping population structure and introgression among recently differentiatedDrosophila melanogasterpopulations
Authors: Coughlan J.M. , Dagilis A.J. , Serrato-Capuchina A. , Elias H. , Peede D. , Isbell K. , Castillo D.M. , Cooper B.S. , Matute D.R.
Published: June 2021

Despite a century of genetic analysis, the evolutionary history underlying patterns of exceptional genetic and phenotypic variation in the model organismDrosophila melanogasterremains poorly understood. How genetic and phenotypic variation is partitioned across the range ofD. melanogaster, particularly in its putative ancestral range in Subtropical Africa, remains unresolved. Here, we assess patterns of population genetic structure, admixture, mate preference, and genetic incompatibility across a global sample, including 174 new accessions from remote regions within Subtropical Africa. While almost all Out of Africa genomes correspond to a single genetic ancestry, different geographic regions within Africa contain multiple ancestries, with substantial cryptic diversity in Subtropical Africa. Admixture between distinct lineages is prevalent across the range, but admixture rates vary between lineages. Female mate choice within Subtropical Africa is highly polymorphic and behavioral types are not monophyletic. The genetic architecture of mate choice is highly polygenic, including loci associated with neurological development, behavior, olfactory perception, and learning. Finally, we discovered that many segregating putative incompatibilities likely evolved during or after expansion out of Africa. This work contributes to our understanding of the evolutionary history of a key model system, and provides insight into the distribution of polymorphic reproductive barriers.
Mutations in PIKFYVE cause autosomal dominant congenital cataract
Authors: Mei Shaoyi , Wu Yi , Wang Yan , Cui Yubo , Zhang Miao , Zhang Tong , Huang Xiaosheng , Yu Sejie , Yu Tao , Zhao Jun
Published: June 2021

Congenital cataract, an ocular disease predominantly occurring within the first decade of life, is one of the leading causes of blindness in children. Through whole exome sequencing of a Chinese family with congenital cataract, we identified a disease-causing mutation (p.G1943E) in PIKFYVE, which affecting the PIP kinase domain of the PIKfyve protein. We demonstrated that heterozygous/homozygous disruption of PIKfyve kinase domain, instead of overexpression of PIKFYVEG1943E in zebrafish mimicked the cataract defect in human patients, suggesting that haploinsufficiency, rather than dominant-negative inhibition of PIKfyve activity caused the disease. Phenotypical analysis of pikfyve zebrafish mutants revealed that loss of Pikfyve caused aberrant vacuolation (accumulation of Rab7+Lc3+ amphisomes) in lens cells, which was significantly alleviated by treatment with the V-ATPase inhibitor bafilomycin A1 (Baf-A1). Collectively, we identified PIKFYVE as a novel causative gene for congenital cataract and demonstrated the potential application of Baf-A1 in treatment of congenital cataract.
SARS-CoV-2 Variants are Selecting for Spike Protein Mutations that Increase Protein Stability
Authors: Shorthouse David , Hall Benjamin. A.
Published: June 2021

The emergence of SARS-CoV-2 in 2019 has caused severe disruption and a huge number of human deaths across the globe. As the pandemic spreads, a natural result is the emergence of variants with a variety of amino acid mutations. Variants of SARS-CoV-2 with mutations in their spike protein may result in an increased infectivity, increased lethality, or immune escape, and whilst many of these properties can be explained through changes to binding affinity or changes to post-translational modification, many mutations have no known biophysical impact on the structure of protein. The Gibbs free energy of a protein represents a measure of protein stability, with an increased stability resulting in a protein that is more thermodynamically stable, and more robust to changes in external environment.

Here we show that mutations in the spike proteins of SARS-CoV-2 are selecting for amino acid changes that result in a more stable protein than expected by chance. We calculate all possible mutations in the SARS-CoV-2 spike protein, and show that many variants are more stable than expected when compared to the background, indicating that protein stability is an important consideration for the understanding of SARS-CoV-2 evolution. Variants exhibit a range of stabilities, and we further suggest that some stabilising mutations may be acting as a “counterbalance” to destabilising mutations that have other properties, such as increasing binding site affinity for the human ACE2 receptor. We suggest that protein folding calculations offer a useful tool for early identification of advantageous mutations.
Circulating multimeric immune complexes drive immunopathology in COVID-19
Authors: Ankerhold Jakob , Giese Sebastian , Kolb Philipp , Maul-Pavicic Andrea , Voll Reinhard E. , Göppert Nathalie , Ciminski Kevin , Kreutz Clemens , Lother Achim , Salzer Ulrich , Bildl Wolfgang , Welsink Tim , Morgenthaler Nils G. , Grawitz Andrea Busse , Huzly Daniela , Schwemmle Martin , Hengel Hartmut , Falcone Valeria
Published: June 2021

A dysregulated immune response with high levels of SARS-CoV-2 specific IgG antibodies characterizes patients with severe or critical COVID-19. Although a robust IgG response is traditionally considered to be protective, excessive triggering of activating Fc-gamma-receptors (FcγRs) could be detrimental and cause immunopathology. Here, we document that patients who develop soluble circulating IgG immune complexes (sICs) during infection are subject to enhanced immunopathology driven by FcγR activation. Utilizing cell-based reporter systems we provide evidence that sICs are predominantly formed prior to a specific humoral response against SARS-CoV-2. sIC formation, together with increased afucosylation of SARS-CoV-2 specific IgG eventually leads to an enhanced CD16 (FcγRIII) activation of immune cells reaching activation levels comparable active systemic lupus erythematosus (SLE) disease. Our data suggest a vicious cycle of escalating immunopathology driven by an early formation of sICs in predisposed patients. These findings reconcile the seemingly paradoxical findings of high antiviral IgG responses and systemic immune dysregulation in severe COVID-19.

Clinical implications

The identification of sICs as drivers of an escalating immunopathology in predisposed patients opens new avenues regarding intervention strategies to alleviate critical COVID-19 progression.

Graphical abstract

A vicious cycle of immunopathology in COVID-19 patients is driven by soluble multimeric immune complexes (sICs). SARS-CoV-2 infection triggers sIC formation in prone individuals. Activation of FcγRIII/CD16 expressing immune cells by sICs precedes a humoral response to SARS-CoV2 infection. sICs and infection add to IgG afucosylation, further enhancing FcγRIII/CD16 activation by opsonized targets. High inflammation induces further sIC mediated immune cell activation ultimately leading to an escalating immunopathology.
Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) Up to 15 Months Post-Infection
Authors: Patterson Bruce K. , Francisco Edgar B. , Yogendra Ram , Long Emily , Pise Amruta , Rodrigues Hallison , Hall Eric , Herrara Monica , Parikh Purvi , Guevara-Coto Jose , Triche Timothy J. , Scott Paul , Hekmati Saboor , Maglinte Dennis , Chang Xaiolan , Mora-Rodríguez Rodrigo A , Mora Javier
Published: June 2021

The recent COVID-19 pandemic is a treatment challenge in the acute infection stage but the recognition of chronic COVID-19 symptoms termed post-acute sequelae SARS-CoV-2 infection (PASC) may affect up to 30% of all infected individuals. The underlying mechanism and source of this distinct immunologic condition three months or more after initial infection remains elusive. Here, we investigated the presence of SARS-CoV-2 S1 protein in 46 individuals. We analyzed T-cell, B-cell, and monocytic subsets in both severe COVID-19 patients and in patients with post-acute sequelae of COVID-19 (PASC). The levels of both intermediate (CD14+, CD16+) and non-classical monocyte (CD14Lo, CD16+) were significantly elevated in PASC patients up to 15 months post-acute infection compared to healthy controls (P=0.002 and P=0.01, respectively). A statistically significant number of non-classical monocytes contained SARS-CoV-2 S1 protein in both severe (P=0.004) and PASC patients (P=0.02) out to 15 months post-infection. Non-classical monocytes were sorted from PASC patients using flow cytometric sorting and the SARS-CoV-2 S1 protein was confirmed by mass spectrometry. Cells from 4 out of 11 severe COVID-19 patients and 1 out of 26 PASC patients contained ddPCR+ peripheral blood mononuclear cells, however, only fragmented SARS-CoV-2 RNA was found in PASC patients. No full length sequences were identified, and no sequences that could account for the observed S1 protein were identified in any patient. Non-classical monocytes are capable of causing inflammation throughout the body in response to fractalkine/CX3CL1 and RANTES/CCR5.
Progression and Resolution of SARS-CoV-2 Infection in Golden Syrian Hamsters
Authors: Mulka Kathleen R. , Beck Sarah E. , Solis Clarisse V. , Johanson Andrew L. , Queen Suzanne E. , McCarron Megan E. , Richardson Morgan R. , Zhou Ruifeng , Marinho Paula , Jedlicka Anne , Guerrero-Martin Selena , Shirk Erin N. , Braxton Alicia , Brockhurst Jacqueline , Creisher Patrick S. , Dhakal Santosh , Brayton Cory F. , Veenhuis Rebecca T. , Metcalf Pate Kelly A. , Karakousis Petros C. , Klein Sabra L. , Jain Sanjay K. , Tarwater Patrick M. , Pekosz Andrew S. , Villano Jason S. , Mankowski Joseph L. ,   for the Johns Hopkins COVID-19 Hamster Study Group
Published: June 2021

To catalyze SARS-CoV-2 research including development of novel interventive and preventive strategies, we characterized progression of disease in depth in a robust COVID-19 animal model. In this model, male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 USA-WA1/2020. Groups of inoculated and mock-inoculated uninfected control animals were euthanized at day 2, 4, 7, 14, and 28 days post-inoculation to track multiple clinical, pathology, virology, and immunology outcomes. SARS-CoV-2-inoculated animals consistently lost body weight during the first week of infection, had higher lung weights at terminal timepoints, and developed lung consolidation per histopathology and quantitative image analysis measurements. High levels of infectious virus and viral RNA were reliably present in the respiratory tract at days 2 and 4 post-inoculation, corresponding with widespread necrosis and inflammation. At day 7, when infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses (type II hyperplasia) dominated in the lung. These lesions resolved over time, with only residual epithelial repair evident by day 28 post-inoculation. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19 using the hamster COVID-19 model.
Performance characteristics of next-generation sequencing for antimicrobial resistance gene detection in genomes and metagenomes
Authors: Rooney Ashley M. , Raphenya Amogelang R. , Melano Roberto G. , Seah Christine , Yee Noelle R. , MacFadden Derek R. , McArthur Andrew G. , Schneeberger Pierre H.H. , Coburn Bryan
Published: June 2021

Short-read sequencing provides a culture-independent method for the detection of antimicrobial resistance (AMR) genes from single bacterial genomes and metagenomic samples. However, the performance characteristics of these approaches have not been systematically characterized. We compared assembly- and read-based approaches to determine sensitivity, positive predictive value, and sequencing limits of detection required for AMR gene detection in an Escherichia coli ST38 isolate spiked into a synthetic microbial community at varying abundances. Using an assembly-based method the limit of detection was 15X genome coverage. We are confident in AMR gene detection at target relative abundances of 100% to 1%, where a target abundance of 1% would require assembly of approximately 30 million reads to achieve 15X target coverage. Recent studies assessing AMR gene content in metagenomic samples may be inadequately sequenced to achieve high sensitivity. Our study informs future sequencing projects and analytical strategies for genomic and metagenomic AMR gene detection.
Hybrid assembly using ultra-long reads resolves repeats and completes the genome sequence of a laboratory strain of Staphylococcus aureus subsp. aureus RN4220
Authors: Panthee Suresh , Hamamoto Hiroshi , Paudel Atmika , Kaito Chikara , Suzuki Yutaka , Sekimizu Kazuhisa
Published: June 2021

Staphylococcus aureus RN4220 has been extensively used by staphylococcal researchers as an intermediate strain for genetic manipulation due to its ability to accept foreign DNA. Despite its wide use in laboratories, its complete genome is not available. In this study, we used the hybrid genome assembly approach using the minION long reads and Illumina short reads to sequence the complete genome of S. aureus RN4220. The comparative analysis of the annotated complete genome showed the presence of 39 genes fragmented in the previous assembly, many of which were located near the repeat regions. Using RNA-Seq reads, we showed that a higher number of reads could be mapped to the complete genome than the draft genome and the gene expression profile obtained using the complete genome also differs from that obtained from the draft genome. Furthermore, by comparative transcriptomic analysis, we showed the correlation between expression levels of staphyloxanthin biosynthetic genes and the production of yellow pigment. This study highlighted the importance of long reads in completing the microbial genomes, especially those possessing repetitive elements.
Laminarin-triggered defence responses are geographically dependent for natural populations ofSolanum chilense
Authors: Kahlon Parvinderdeep S. , Förner Andrea , Muser Michael , Oubounyt Mhaned , Gigl Michael , Hammerl Richard , Baumbach Jan , Hückelhoven Ralph , Dawid Corinna , Stam Remco
Published: June 2021

Natural plant populations are polymorphic and show intraspecific variation in resistance properties against pathogens. The activation of the underlying defence responses can depend on variation in perception of pathogen-associated molecular patterns or elicitors. To dissect such variation, we evaluated the responses induced by laminarin, (a glucan, representing an elicitor from oomycetes) in the wild tomato speciesSolanum chilenseand correlated this to observed infection frequencies ofPhytophthora infestans.

We measured reactive oxygen species burst and levels of diverse phytohormones upon elicitation in 83 plants originating from nine populations. We found high diversity in basal and elicitor-induced levels of each component. Further we generated linear models to explain the observed infection frequency ofP. infestans. The effect of individual components differed dependent on the geographical origin of the plants. We found that the resistance in the southern coastal region, but not in the other regions is directly correlated to ethylene responses and confirmed this positive correlation using ethylene inhibition assays.

Our findings reveal high diversity in the strength of defence responses within a species and the involvement of different components with a quantitatively different contribution of individual components to resistance in geographically separated populations of a wild plant species.

Highlight

Large-scale screenings reveal geographically distinct intraspecific differences in the dominant physiological pathogen defence responses upon glucan elicitor treatment in a wild tomato species.
IFT20 is critical for early chondrogenesis during endochondral ossification
Authors: Yamaguchi Hiroyuki , Kitami Megumi , Uchima Koecklin Karin H. , He Li , Wang Jianbo , Perrien Daniel S. , Lagor William R. , Komatsu Yoshihiro
Published: June 2021

Ciliogenic components, such as the family of intraflagellar transport (IFT) proteins, are recognized to play key roles in endochondral ossification, a critical process to form most bones. However, it remains unclear how each IFT protein performs its unique function to regulate endochondral ossification. Here, we show that intraflagellar transport 20 (IFT20) is required for early chondrogenesis. Utilizing three osteo-chondrocyte lineage-specific Cre mice (Prx1-Cre, Col2-Cre and Aggrecan-CreERT2), we deleted Ift20 to examine its function. While chondrocyte-specific Ift20 deletion with Col2-Cre or Aggrecan-CreERT2 drivers did not cause overt skeletal defects, mesoderm-specific Ift20 deletion using Prx1-Cre (Ift20:Prx1-Cre) resulted in shortened limb outgrowth. Although primary cilia were not formed in Ift20:Prx1-Cre mice, ciliary Hedgehog signaling was only moderately affected. Interestingly, loss of Ift20 lead to upregulation of Fgf18 expression resulting in ERK1/2 activation and sustained Sox9 expression, thus preventing endochondral ossification. Inhibition of enhanced phospho-ERK1/2 activation partially rescued defective chondrogenesis in Ift20 mutant cells, supporting an important role for FGF signaling. Our findings demonstrate a novel mechanism of IFT20 in early chondrogenesis during endochondral ossification.
Developmental onset of a cerebellar-dependent forward model of movement in motor thalamus
Authors: Dooley James C. , Sokoloff Greta , Blumberg Mark S.
Published: June 2021

To execute complex behavior with temporal precision, adult animals use internal models to predict the sensory consequences of self-generated movement. Here, taking advantage of the unique kinematic features of twitches—the brief, discrete movements of active sleep—we captured the developmental onset of a cerebellar-dependent internal model. Using rats at postnatal days (P) 12, P16, and P20, we compared neural activity in two thalamic structures: the ventral posterior (VP) and ventral lateral (VL) nuclei, both of which receive somatosensory input but only the latter of which receives cerebellar input. At all ages, twitch-related activity in VP lagged behind movement, consistent with sensory processing; similar activity was observed in VL through P16. At P20, however, VL activity precisely mimicked the twitch itself, a pattern of activity that depended on cerebellar input. Altogether, these findings implicate twitches in the development and refinement of internal models of movement.
Revisiting the STRmix™likelihood ratio probability interval coverage considering multiple factors
Authors: Bright Jo-Anne , Lee Shan-I , Buckleton John , Taylor Duncan
Published: June 2021

In previously reported work a method for applying a lower bound to the variation induced by the Monte Carlo effect was trialled. This is implemented in the widely used probabilistic genotyping system, STRmix™. The approach did not give the desired 99% coverage.

However, the method for assigning the lower bound to the MCMC variability is only one of a number of layers of conservativism applied in a typical application. We tested all but one of these sources of variability collectively and term the result the near global coverage. The near global coverage for all tested samples was greater than 99.5% for inclusionary averageLRs of known donors. This suggests that when included in the probability interval method the other layers of conservativism are more than adequate to compensate for the intermittent underperformance of the MCMC variability component. Running for extended MCMC accepts was also shown to result in improved precision.
DatumKB: A Database of Biological Experimental Results
Authors: Knapp Merrill , McCarthy Tim , Talcott Carolyn
Published: June 2021

1.

DatumKB is a freely accessible database of experimental results involving the function and regulation of human proteins in cultured cells. The results are manually curated from biological research literature using a shorthand language and stored as datums. Datums were originally designed to be used as evidence for rules in a Pathway Logic model of intracellular signal transduction (STM8, http://pl.csl.sri.com/online.html) (1). They are independent units that can be understood by biologists, traced back to their source, and have enough structure to be interrogated computationally. The information is expressed using a controlled vocabulary with links to well known databases such as HUGO Gene Nomenclature Committee (HGNC), UniProt, PubChem, and Cellosaurus. DatumKB can be searched using a query interface and the results can be downloaded in the original datum format, a simplified text format, or a JSON file. Links to detailed documentation of datum structure and a tutorial for the search engine are provided.

Database URL

https://datum.csl.sri.com
The WZA: A window-based method for characterizing genotype-environment association
Authors: Booker Tom R. , Yeaman Sam , Whitlock Michael C.
Published: June 2021

Genotype environment association (GEA) studies have the potential to elucidate the genetic basis of local adaptation in natural populations. Specifically, GEA approaches look for a correlation between allele frequencies and putatively selective features of the environment. Genetic markers with extreme evidence of correlation with the environment are presumed to be tagging the location of alleles that contribute to local adaptation. In this study, we propose a new method for GEA studies called the weighted-Z analysis (WZA) that combines information from closely linked sites into analysis windows in a way that was inspired by methods for calculating FST. We analyze simulations modelling local adaptation to heterogeneous environments either using a GEA method that controls for population structure or an uncorrected approach. In the majority of cases we tested, the WZA either outperformed single-SNP based approaches or performed similarly. The WZA outperformed individual SNP approaches when the measured environment is not perfectly correlated with the true selection pressure or when a small number of individuals or demes was sampled. We apply the WZA to previously published data from lodgepole pine and identified candidate loci that were not found in the original study.
Single Molecule Studies and Kinase Activity Measurements Reveal Regulatory Interactions between the Master Kinases Phosphoinositide-Dependent-Kinase-1 (PDK1), Protein Kinase B (AKT1/PKB) and Protein Kinase C (PKCα)
Authors: Gordon Moshe T. , Ziemba Brian P. , Falke Joseph J.
Published: June 2021

Leukocyte migration is controlled by a leading edge chemosensory pathway that generates the regulatory lipid PIP3, a growth signal, thereby driving leading edge expansion up attractant gradients toward sites of infection, inflammation, or tissue damage. PIP3 also serves as an important growth signal in growing cells and oncogenesis. The kinases PDK1, AKT1/PKB and PKCα are key components of a plasma membrane-based PIP3 and Ca2+ signaling circuit that regulates these processes. PDK1 and AKT1 are recruited to the membrane by PIP3, while PKCα is recruited to the membrane by Ca2+. All three of these master kinases phosphoregulate an array of protein targets. For example, PDK1 activates AKT1, PKCα and other AGC kinases by phosphorylation at key sites. PDK1 is known to form PDK1:AKT1 and PDK1:PKCα heterodimers stabilized by a PIF interaction between the PDK1 PIF pocket and the PIF motif of the AGC binding partner. Here we present the first, to our knowledge, single molecule studies of full length PDK1 and AKT1 on target membrane surfaces, as well as their interaction with full length PKCα. The findings show that membrane-bound PDK1:AKT1 and PDK1:PKCα heterodimers form under physiological conditions, and are stabilized by PIF interaction. PKCα exhibits 8-fold higher PDK1 affinity than AKT1, thus PKCα competitively displaces AKT1 from PDK1:AKT1 heterodimers. Ensemble activity measurements under matched conditions reveal that PDK1 activates AKT1 via a cis mechanism by phosphorylating an AKT1 molecule in the same PDK1:AKT1 heterodimer, while PKCα acts as a competitive inhibitor of this phosphoactivation reaction by displacing AKT1 from PDK1. Overall, the findings provide new insights into molecular and regulatory interactions of the three master kinases on their target membrane, and suggest that the recently described tumor suppressor activity of PKC may arise from its ability to downregulate PDK1-AKT1 phosphoactivation in the PIP3-PDK1-AKT1-mTOR pathway linked to cell growth and oncogenesis.

STATEMENT OF SIGNIFICANCE

This work investigates three master kinases that play central roles in guiding white blood cell migration to sites of infection, inflammation or tissue damage. More broadly, the same kinases help regulate production of a cell growth signal, and may trigger cancer when dysregulated. Using powerful single molecule methods, the work detects and analyzes the interactions between the three purified kinases on their target membrane surface. The findings reveal functionally important differences between pairwise binding affinities of different binding partners. Additional studies reveal that the highest affinity kinase can disrupt and inhibit the activated complex formed by association of the other two kinases. Such inhibition is proposed to help prevent cancer by limiting growth signal production by the activated complex.
An acetyl-click screening platform identifies a small molecule inhibitor of Histone Acetyltransferase 1 (HAT1) with anti-tumor activity
Authors: Gruber Joshua J. , Rangarajan Amithvikram , Chou Tristan , Geller Benjamin S. , Banuelos Selene , Greenhouse Robert , Snyder Michael P. , Lipchik Andrew M.
Published: June 2021

HAT1 is a central regulator of chromatin synthesis that acetylates nascent histone H3:H4 tetramers in the cytoplasm. It may have a role in cancer metabolism by linking cytoplasmic production of acetyl-CoA to nuclear acetyl flux. This is because the HAT1 di-acetylation mark is not propagated in chromatin and instead is de-acetylated after nascent histone insertion into chromatin. Thus, HAT1 likely provides a nuclear source of free acetate that may be recycled to acetyl-CoA for nuclear acetylation reactions. Correspondingly, suppression of HAT1 protein expression impairs tumor growth. To ascertain whether targeting HAT1 is a viable anti-cancer treatment strategy we sought to identify small molecule inhibitors of HAT1. We developed a high-throughput HAT1 acetyl-click assay to facilitate drug discovery and enzymology. Screening of small molecules computationally predicted to bind the active site led to the discovery of multiple riboflavin analogs that inhibited HAT1 enzymatic activity by competing with acetyl-CoA binding. These hits were refined by synthesis and testing over 70 analogs, which yielded structure-activity relationships. The isoalloxazine core was required for enzymatic inhibition, whereas modifications of the ribityl sidechain improved enzymatic potency and cellular growth suppression. These efforts resulted in a lead compound (JG-2016) that suppressed growth of human cancer cells linesin vitroand impaired tumor growthin vivo. This is the first report of a small molecule inhibitor of the HAT1 enzyme complex and represents a step towards targeting this pathway for cancer therapy.
Work-related practices of local managers of live music events in Ostwestfalen-Lippe (OWL) and their impact on cultural participation
Authors: Flath Beate , Momen Pour Tafreshi Maryam
Published: June 2021

Purpose

The purpose of this article is to illuminate the relations of work-related practices of local managers of live music events in Ostwestfalen-Lippe (OWL) and barriers and needs of vulnerable customers (VC) in order to explore possibilities to increase cultural participation of VC.

Design/methodology/approach

This article explores work-related practices of managers of live music events in OWL and asks if and to what extent these practices have an influence on the cultural participation of “vulnerable customers” (VC). It combines the findings of two studies: a) an explorative investigation on the work-related self-conceptions of managers of live music events in OWL (Study 1), and b) a sub-project on cultural participation of VC, which is part of the research project “kulturPreis. Increasing cultural participation through innovative and economically sustainable pricing concepts”, funded by the German Federal Ministry of Education and Research (Study 2).

Findings

It can be stated that there is an imbalance of knowledge: while VC tend to have a clear understanding of which barriers are the responsibility of managers of live music events, managers tend to lack knowledge regarding the needs of VC, and regarding the interrelationships between financial and social barriers facing them. Whether this knowledge and understanding can be developed in the future depends on the possibilities of exchanges between managers of live music events, cultural institutions, welfare organisations, political institutions and not least VC.

Originality/value

Based on these studies, this article combines different approaches by linking work-related practices of managers of live music events with cultural participation of VC.
The information content of managerial insider trading: evidence from analyst forecasts
Authors: Esqueda Omar , Ngo Thanh , Wang Daphne
Published: June 2021

Purpose

This paper examines the effect of managerial insider trading on analyst forecast accuracy, dispersion and bias. Specifically, the authors test whether insider-trading information is positively associated with the precision of earnings forecasts. In addition, this relationship between Regulation Fair Disclosure (FD) and the Galleon insider trading case is examined.

Design/methodology/approach

Pooled ordinary least squares (Pooled OLS) rregressions with year-fixed effects, firm-fixed effects, and firm-level clustered standard errors are used. Our proxies for forecast precision are regressed on alternative measures of insider trading activities and a vector of control variables.

Findings

Insider-trading information is positively associated with the precision of earnings forecasts. Analysts provide better forecast accuracy, less forecast dispersion and lower forecast bias among firms with insider trading in the six months leading to the forecast issues. In addition, bullish (bearish) insider trades are associated with increased (decreased) forecast bias. Insider trading information complements analysts' independent opinion and increases the precision of their forecast.

Practical implications

Regulators may pursue rules that promote the rapid disclosure of managerial insider trades, particularly given the increasing availability of Internet tools. Securities regulators may attempt to increase transparency and enhance the reporting procedures of corporate insiders, for example, using Internet sources with direct release to the public to ensure more timely information dissemination.

Originality/value

The authors document a positive association between earnings forecast precision and managerial insider trading up to six months prior to the forecast issue. This relationship is stronger after the Securities and Exchange Commission (SEC) prohibited the selective disclosure of material nonpublic information through Regulation FD. In addition, the association between insider trading and forecast accuracy has weakened after the Galleon insider trading case.
A new fuzzy random multi-objective portfolio model with different entropy measures using fuzzy programming based on artificial bee colony algorithm
Authors: Deng Xue , He Xiaolei , Huang Cuirong
Published: June 2021

Purpose

This paper proposes a fuzzy random multi-objective portfolio model with different entropy measures and designs a hybrid algorithm to solve the proposed model.

Design/methodology/approach

Because random uncertainty and fuzzy uncertainty are often combined in a real-world setting, the security returns are considered as fuzzy random numbers. In the model, the authors also consider the effects of different entropy measures, including Yager's entropy, Shannon's entropy and min-max entropy. During the process of solving the model, the authors use a ranking method to convert the expected return into a crisp number. To find the optimal solution efficiently, a fuzzy programming technique based on artificial bee colony (ABC) algorithm is also proposed.

Findings

(1) The return of optimal portfolio increases while the level of investor risk aversion increases. (2) The difference of the investment weights of the optimal portfolio obtained with Yager's entropy are much smaller than that of the min–max entropy. (3) The performance of the ABC algorithm on solving the proposed model is superior than other intelligent algorithms such as the genetic algorithm, differential evolution and particle swarm optimization.

Originality/value

To the best of the authors' knowledge, no effect has been made to consider a fuzzy random portfolio model with different entropy measures. Thus, the novelty of the research is constructing a fuzzy random multi-objective portfolio model with different entropy measures and designing a hybrid fuzzy programming-ABC algorithm to solve the proposed model.