bluuebunny/crossref_metadata_2025_split huggingface dataset:
Statistical and functional convergence of common and rare variant risk for autism spectrum disorders at chromosome 16p
Authors: Weiner Daniel J. , Ling Emi , Erdin Serkan , Tai Derek J.C. , Yadav Rachita , Grove Jakob , Fu Jack M. , Nadig Ajay , Carey Caitlin E. , Baya Nikolas , Bybjerg-Grauholm Jonas ,   iPSYCH Consortium,   ASD Working Group of the Psychiatric Genomics Consortium,   ADHD Working Group of the Psychiatric Genomics Consortium, Berretta Sabina , Macosko Evan Z. , Sebat Jonathan , O’Connor Luke J. , Hougaard David M. , Børglum Anders D. , Talkowski Michael E. , McCarroll Steve A. , Robinson Elise B. 
Published: March 2022

AbstractThe dominant human genetics paradigm for converting association to mechanism (“variant-to-function”) involves iteratively mapping individual associations to specific SNPs and to the proximal genes through which they act. In contrast, here we demonstrate the feasibility of extracting biological insight from a very large (>10Mb) region of the genome, and leverage this approach to derive insight into autism spectrum disorder (ASD). Using a novel statistical framework applied in an unbiased scan of the genome, we identified the 33Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of common polygenic risk for ASD. This region includes the recurrent 16p11.2 copy number variant (CNV) – one of the largest single genetic risk factors for ASD, and whose pathogenic mechanisms are undefined. Analysis of bulk and single-cell RNA-sequencing data from post-mortem human brain samples revealed that common polygenic risk for ASD within 16p associated with decreased average expression of genes throughout this 33-Mb region. Similarly, analysis of isogenic neuronal cell lines with CRISPR/Cas9-mediated deletion of 16p11.2 revealed that the deletion also associated with depressed average gene expression across 16p. The effects of the rare deletion and diffuse common variation were correlated at the level of individual genes. Finally, analysis of chromatin contact patterns by Hi-C revealed patterns which may explain this transcriptional convergence, including elevated contact throughout 16p, and between 16p11.2 and a distal region on 16p (Mb 0-5.2) which showed the greatest gene expression changes in both the common and rare variant analyses. These results demonstrate that elevated 3D chromatin contact may coordinate genetic and transcriptional disease liability across large genomic regions, exemplifying a novel approach for extracting biological insight from genetic association data. As applied to ASD, our analyses highlight the 33Mb p-arm of chromosome 16 as a novel locus for ASD liability and provide insight into disease liability originating from the 16p11.2 CNV.
Phosphoprotein Phosphatase Activity Positively Regulates Oligomeric Pyrin to Trigger Inflammasome Assembly in Phagocytes
Authors: Malik Haleema S. , Magnotti Flora , Loeven Nicole A. , Delgado Jose M. , Kettenbach Arminja N. , Henry Thomas , Bliska James B. 
Published: March 2022

AbstractPyrin is a pattern-recognition receptor in phagocytes that triggers capase-1 inflammasome assembly in response to bacterial toxins and effectors that inactivate RhoA. Pyrin contains oligomerization domains and is negatively regulated by phosphorylation of two residues, S205 and S241 (murine) or S208 and S242 (human), via the kinases PKN1/2, which are activated by RhoA. Familial Mediterranean Fever (FMF) is caused by phagocyte production of pyrin gain of function variants, which have a lower threshold for inflammasome assembly upon RhoA-PKN axis inhibition. Inactivation of the RhoA-PKN axis removes negative regulation but a phosphoprotein phosphatase (PPP) is needed to positively regulate pyrin. No PPP that dephosphorylates pyrin has been identified, oligomerization of murine pyrin has not been studied, and the phosphorylation status of oligomeric pyrin is unknown. We used murine macrophages and FMF patient’s monocytes combined with the use of bacterial agonists and chemical inhibitors, native PAGE, phospho-specific antibodies and siRNA knockdowns to determine if a PPP positively regulates oligomeric pyrin. Results with broadly-specific inhibitors indicate that PPP activity is required to dephosphorylate murine and human pyrin in wild type or FMF patient’s phagocytes. Findings from native PAGE show that murine pyrin forms oligomers that are phosphorylated on S205 prior to RhoA inactivation. Inhibitors cause reduced mobility of murine pyrin on native PAGE and hyperphosphorylation of S242 in human pyrin, suggesting a PPP constitutively counterbalances PKN to keep the second site hypophosphorylated. Data from siRNA knockdown experiments implicate PP2A in dephosphorylation of S205 and positive regulation of pyrin in response to RhoA inactivation.Key pointsMurine pyrin is oligomeric and phosphorylated on S205 prior to inflammasome assemblyPPP activity positively regulates pyrin inflammasome assembly in mice and humansThe alpha and beta subunits of PP2A dephosphorylate murine pyrin S205 in macrophages
Stem cell homeostasis regulated by hierarchy and neutral competition
Authors: Nakamuta Asahi , Yoshido Kana , Naoki Honda 
Published: March 2022

AbstractTissue stem cells maintain themselves through self-renewal while constantly supplying differentiating cells. As a mechanism of stem cell homeostasis, two distinct models were proposed: the classical model states that there are hierarchy among stem cells and master stem cells provide stem cells by asymmetric divisions, whereas the recent model states that stem cells are equipotent and neutrally competing each other. However, its mechanism is still controversial in several tissues and species. Here, we developed a mathematical model linking these two models. Our theoretical analysis showed that the model with the hierarchy and neutral competition, called the hierarchical neutral competition (hNC) model, exhibited bursts in clonal expansion, unlike existing models. Furthermore, the scaling law in clone size distribution, thought to be a unique characteristic of the recent model, was satisfied in the hNC model. Based on these findings, we proposed a criterion for distinguishing the three models by experiments.
A multiple comorbidities mouse model to assess atherosclerosis progression following lung infection in ApoE deficient mice
Authors: Bartlett Benjamin , Lee Silvia , Ludewick Herbert P , Siew Teck , Verma Shipra , Waterer Grant , Corrales-Medina Vicente F. , Dwivedi Girish 
Published: March 2022

ABSTRACTBackgroundInflammation is a risk factor for atherosclerosis progression. Hospitalisation for pneumonia is associated with increased risk of cardiovascular disease. Herein, we describe a multiple comorbidities murine model to study the impact of bacterial pneumonia on atherosclerosis.MethodsFirstly, a minimal infectious dose of Streptococcus pneumoniae (TIGR4 strain) to produce clinical pneumonia with a low mortality rate (20%) was established. C57Bl/6 ApoE-/- mice were fed a high-fat diet prior to administering intranasally 105 colony forming units of TIGR4 or phosphate buffered saline (PBS). At days 2, 7 and 28 post inoculation (PI), the lungs of mice were imaged by MRI and PET. Mice were euthanised and investigated for changes in systemic inflammation and changes in lung morphology using ELISA, Luminex assay and real-time PCR.ResultsTIGR4 inoculated mice presented with varying degreess of lung infiltrate, pleural effusion and consolidation on MRI at all timepoints up to 28 days PI. Moreover, PET scans identified significantly higher FDG uptake in the lungs of TIGR4 inoculated mice up to 28 days PI. Majority (90%) TIGR4-inoculated mice developed pneumococcal-specific IgG antibody response at 28 days PI. Consistent with these observations, TIGR4 inoculated mice displayed significantly increased inflammatory gene expression (IL-1β & IL6) in the lungs and significantly increased levels of circulating inflammatory protein (CCL3) at 7- and 28-days PI respectively.ConclusionsOur mouse model presents a discovery tool to understand the link between acute infections, including pneumonia, and increased cardiovascular disease risk in humans with inflammation as the mechanistic catalyst.Graphical Abstract
Epigenetic and genetic population structure is coupled in a marine invertebrate
Authors: Silliman Katherine , Spencer Laura H. , White Samuel J. , Roberts Steven B. 
Published: March 2022

AbstractDelineating the relative influence of genotype and the environment on DNA methylation is critical for characterizing the spectrum of organism fitness as driven by adaptation and phenotypic plasticity. In this study, we integrated genomic and DNA methylation data for two distinct Olympia oyster (Ostrea lurida) populations while controlling for within-generation environmental influences. In addition to providing the first characterization of genome-wide DNA methylation patterns in the oyster genusOstrea, we identified 3,963 differentially methylated loci between populations. Our results show a clear coupling between genetic and epigenetic patterns of variation, with 27% of variation in inter-individual methylation differences explained by genotype. Underlying this association are both direct genetic changes in CpGs (CpG-SNPs) and genetic variation with indirect influence on methylation (mQTLs). The association between genetic and epigenetic patterns breaks down when comparing measures of population divergence at specific genomic regions, which has implications for the methods used to study epigenetic and genetic coupling in marine invertebrates.Significance statementWe know that genotype and epigenetic patterns are primarily responsible for phenotype, yet there is a lack of understanding to what degree the two are linked. Here we characterized the mechanisms and the degree by which genetic variation and DNA methylation variation are coupled in a marine invertebrate, with almost a third of the methylation variation attributable to genotype. This study provides a framework for future studies in environmental epigenetics to take genetic variation into account when teasing apart the drivers of phenotypic variation. By identifying methylation variation that cannot be attributed to genotype or environmental changes during development, our results also highlight the need for future research to characterize molecular mechanisms adjacent to genetic adaptation for producing long-term shifts in phenotype.
Proteomic analysis reveals microvesicles containing NAMPT as mediators of radiation resistance in glioma
Authors: Panizza Elena , Regalado Brandon D. , Wang Fangyu , Nakano Ichiro , Vacanti Nathaniel M. , Cerione Richard A. , Antonyak Marc A. 
Published: March 2022

AbstractGlioma is a malignant brain tumor that is highly resistant to radiation and chemotherapy, where patients survive on average only 15 months after diagnosis. Furthering the understanding of mechanisms leading to radiation resistance of glioma is paramount to identify novel therapeutic targets. Previous studies have shown that glioma stem cells (GSCs) play an important role in promoting radiation resistance and disease recurrence. Herein we analyze the proteomic alterations occurring in patient-derived GSCs upon radiation treatment in order to identify molecular drivers of resistance. We show that proteome changes upon radiation accurately predict the resistance status of the cells, whereas resistance to radiation does not correlate with glioma transcriptional subtypes. We further show that the radio-resistant GSC-267 cell line sheds microvesicles (MVs) enriched in the metabolic enzyme nicotinamide phosphoribosyltransferase (NAMPT). These MVs can be transferred to recipient fibroblasts and radio-sensitive GSCs, enhancing their intracellular total NAD+ and NADH level, and their ability to proliferate when cultured in low serum, treated with a radio-mimetic drug or irradiated. The NAMPT enzymatic inhibitor FK-866 blocked the ability of MVs from GSC-267 cells to mediate these effects. Similarly, GSC-267 cells where NAMPT was knocked-down using shRNA, which produced MVs depleted of this enzyme, were unable to promote cell proliferation. Collectively, our findings demonstrates that proteome-level regulation can accurately predict the radio-resistance status of GSCs, and identifies NAMPT transfer via MVs as a mechanism for spreading radiation resistance within the glioma tumor microenvironment.SignificanceThe highly aggressive and deadly brain cancer glioma is commonly resistant to standard chemo- and radio-therapy. We used systems biology approaches to study patient-derived glioma stem cells (GSCs), which are known to be responsible for therapeutic resistance, and cell-to-cell communication mediated by extracellular vesicles (EVs), which plays an important role in tumor progression. Analysis of the proteome of GSCs and of the EVs they release led us to determine that the EV-mediated transfer of the metabolic enzyme nicotinamide phosphorybosyltransferase (NAMPT) from radio-resistant to less aggressive cells confers resistance to radiation. Our findings identify a mechanism of therapy resistance in glioma, and suggest that NAMPT inhibition could enhance the efficacy of radiation for the treatment of glioma.
Filter paper disks as a matrix for manipulation of recombinant proteins
Authors: Ball Eric H. , Basilone Nicoletta T. 
Published: March 2022

AbstractFilter paper provides an excellent matrix for retention of proteins containing a cellulose binding domain. To use this capability for manipulating recombinant fusion proteins, binding and elution parameters were explored and procedures developed for small scale purification, modification and assay. Proteins were tagged with the cellulose binding domain from theC thermocellumCipB gene via a cleavable linker. Filter paper disks of 6mm diameter were able to bind up to 80 μg protein although there was a substantial dependence on molecular size. Different means of introducing fusion proteins to the disks allow either binding within 20 minutes from microliter volumes or slower binding from milliliter volumes. Elution with protease in small volumes yielded greater than 10 μg amounts with concentrations in the 1-2 mg/ml range. To demonstrate their utility, disks were used for small scale protein purification, covalent modification of protein, immunoprecipitation, and in a binding assay. These versatile methods allow parallel processing of multiple samples and may find many uses when only small amounts of protein are needed.
Agrobacterium mediated transformation and deciphering SNPs in TaLr67 gene homeologs for gene editing in wheat
Authors: Thiyagarajan Karthikeyan , Noguera Luis Miguel , Pacheco Mario , Govindan Velu , Vikram Prashant 
Published: March 2022

AbstractDiseases adversely affect grain yield of crop plants. Leaf rust is a major disease of wheat. As race-specific resistance breaks down, introduction of newer sources of resistance often from older accessions is necessary. Linkage drag from the donor accessions adversely impacts grain yield. As a result, CIMMYT breeding effort has shifted to using durable resistance, also referred to as race non-specific host resistance, which allows slow rusting but maintains grain yield. One of the key genes for durable resistance is Lr67 and the resistant form of this gene is absent in CIMMYT elite lines. Hence, we have initiated efforts to convert the susceptible copy of Lr67 into its resistant form directly in these elite lines using gene editing. This would eliminate backcrossing and thus save time as well as eliminate linkage drag that would accompany the resistant copy of the gene if it were to be introgressed from an older accession. As first steps, we have isolated and sequenced the genomic copies from each of the A, B, and D genome of the Lr67 gene from three elite lines and an experimental line. Identification of more than 50 single nucleotide polymorphisms (SNPs) in the open reading frames (ORF) among these lines would be useful in designing the guide RNA molecules with precision. Further, we have streamlined genetic transformation of these elite lines, a prerequisite step for gene editing.
Bacteriophages Playing Nice: Lysogenic bacteriophage replication stable in the human gut microbiota
Authors: Sutcliffe Steven G. , Reyes Alejandro , Maurice Corinne F. 
Published: March 2022

1.1.AbstractThe human gut is a dense microbial community, of which bacteria and bacteriophages are the majority. Bacteriophages, viruses of bacteria, exist stably, without major fluctuations in the gut of healthy individuals. This stability appears to be due to an absence of ‘kill-the-winner’ dynamics, and the existence of ‘piggy-back-the-winner’ dynamics, where lysogenic replication rather than lytic replication occurs. Revisiting the deep-viral sequencing data of a healthy individual studied over 2.4 years, we were able to improve our understanding of how these dynamics occur in healthy individuals. We assembled prophages from bacterial metagenomic data and show that these prophages were continually switching from lysogenic to lytic replication. Prophages were the source of a stable extracellular phage population continually present in low abundance, in comparison to the lytic-phage population, where taxonomic diversity diverged over 2.4 years. The switch to lytic replication, or prophage induction, appears to occur mostly through spontaneous prophage induction. The observed phage dynamics of regular spontaneous induction are ecologically important as they allow prophages to maintain their ability to replicate, avoiding degradation and their loss from the gut microbiota.1.2.Significance StatementIt has been eight years since Minot and colleagues published their landmark longitudinal study of phages in the gut. In the years following, the bioinformatic field improved in great strides, including the methods of bacterial-genome assembly, phage-identification, and prophage detection. We leveraged the unprecedented deep sequencing of phages in this dataset by adding bacterial assembly and prophage detection analyzes. We show clearly for the first time that ‘piggy-back-the-winner’ dynamics are maintained in the gut through spontaneous prophage induction, and not widespread triggered prophage induction. These dynamics play an important ecological role by creating a stable subpopulation of phages, which could help explain how phages are maintained over the 2.4 years timeframe that this individual was studied.
Achieve a better shape of life: how entrepreneurship gears up life-time well-being
Authors: Zhou Jinyi , Park Jong Gyu , Li Yawen 
Published: March 2022

PurposeAn anomaly of entrepreneurship literature was that, despite serious efforts required to manage a business, few studies had investigated entrepreneurs' health conditions at the end of their careers. This study investigated whether one's entrepreneurship in a lifetime enhanced their health after a career plateau.Design/methodology/approachThe authors tested the main effect and mediating effects of entrepreneurs' life habits and self-esteem, respectively, using two longitudinal representative examples with 8,984 and 12,686 participants.FindingsResults indicated that entrepreneurship significantly improved individuals' general lifetime health condition. Moreover, life habits (e.g. vigorous activities or sports, light activities, drinking habits and diet habits) and self-esteem significantly mediated the relationship between entrepreneurship and lifetime health. Entrepreneurs tended to have better health due to healthier life habits and higher self-esteem than salaried employees. In this paper, the authors also discussed theoretical and practical implications.Originality/valueThe authors proposed and found that, to counter the harsh requirements of entrepreneurial actions, entrepreneurs need to seek personal physical and psychological resources, and these resources can benefit their health even after decades.
Understanding the transformation toward omnichannel logistics in grocery retail: a dynamic capabilities perspective
Authors: Eriksson Ebba , Norrman Andreas , Kembro Joakim 
Published: March 2022

PurposeOmnichannel (OC) logistics is undergoing a significant transformation in grocery retail. To shed light on this important but underresearched phenomenon, this study aims to investigate how grocery retailers transform and why some are more successful in transforming OC logistics.Design/methodology/approachApplying dynamic capabilities as a theoretical lens, a multiple case study was conducted with three grocery retailers at different stages of their transformation.FindingsSix microfoundations of dynamic capabilities were identified as critical for enabling OC transformation. The study highlights important differences in dynamic capabilities, which can be attributed to investment decision-making, governance and creating co-specialization. Finally, the authors propose seven propositions for contextualization of dynamic capabilities for OC transformation in grocery retail.Originality/valueThis study is original by contextualizing microfoundations in grocery OC retailing. The study contributes to theory and practice by showing the value of dynamic capabilities, stressing the important interrelation among a retailer's governance structure, leadership and capability to make investment decisions, increase logistics coordination and co-specialize.
Predation risk can modify the foraging behaviour of frugivorous carnivores: Implications of rewilding apex predators for plant–animal mutualisms
Authors: Burgos Tamara , Fedriani Jose M. , Escribano‐Ávila Gema , Seoane Javier , Hernández‐Hernández Javier , Virgós Emilio 
Published: March 2022

Abstract

Apex predators play key roles in food webs and their recovery can trigger trophic cascades in some ecosystems. Intra‐guild competition can reduce the abundances of smaller predators and perceived predation risk can alter their foraging behaviour thereby limiting seed dispersal by frugivorous carnivores. However, little is known about how plant–frugivore mutualisms could be disturbed in the presence of larger predators.

We evaluated the top‐down effect of the regional superpredator, the Iberian lynx Lynx pardinus, on the number of visits and fruits consumed by medium‐sized frugivorous carnivores, as well as the foraging behaviour of identified individuals, by examining the consumption likelihood and the foraging time.

We carried out a field experiment in which we placed Iberian pear Pyrus bourgaeana fruits beneath fruiting trees and monitored pear removal by frugivorous carnivores, both inside and outside lynx ranges. Using camera traps, we recorded the presence of the red fox Vulpes vulpes, the Eurasian badger Meles meles and the stone marten Martes foina, as well as the number of fruits they consumed and their time spent foraging.

Red fox was the most frequent fruit consumer carnivore. We found there were fewer visits and less fruit consumed by foxes inside lynx ranges, but lynx presence did not seem to affect badgers. We did not observe any stone marten visits inside lynx territories. The foraging behaviour of red foxes was also altered inside lynx ranges whereby foxes were less efficient, consuming less fruit per unit of time and having shorter visits. Local availability of fruit resources, forest coverage and individual personality also were important variables to understand visitation and foraging in a landscape of fear.

Our results show a potential trophic cascade from apex predators to primary producers. The presence of lynx can reduce frugivorous carnivore numbers and induce shifts in their feeding behaviour that may modify the seed dispersal patterns with likely consequences for the demography of many fleshy‐fruited plant species. We conclude that knowledge of the ecological interactions making up trophic webs is an asset to design effective conservation strategies, particularly in rewilding programs.