bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accurate Detection of Convergent Mutations in Large Protein Alignments with ConDor
Authors: Morel Marie , Lemoine Frédéric , Zhukova Anna , Gascuel Olivier 
Published: July 2021

AbstractEvolutionary convergences are observed at all levels, from phenotype to DNA and protein sequences, and changes at these different levels tend to be highly correlated. Notably, convergent and parallel mutations can lead to convergent changes in phenotype, such as changes in metabolism, drug resistance, and other adaptations to changing environments.We propose a two-step approach to detect mutations under convergent evolution in protein alignments. We first select mutations that emerge more often than expected under neutral evolution and then test whether their emergences correlate with the convergent phenotype under study. The first step can be used alone when no phenotype is available, as is often the case with microorganisms. In the first step, a phylogeny is inferred from the data and used to simulate the evolution of each alignment position. These simulations are used to estimate the expected number of mutations under neutral conditions, which is compared to what is observed in the data. Next, using a comparative phylogenetic approach, we measure whether the presence of mutations occurring more often than expected correlates with the convergent phenotype.Our method is implemented in a standalone workflow and a webserver, called ConDor. We apply ConDor to three datasets: sedges PEPC proteins, HIV reverse transcriptase and fish rhodopsin. The results show that the two components of ConDor complement each other, with an overall accuracy that compares favorably to other available tools, especially on large datasets.
Does Communal Breeding Promote an Increase in Social Immunity in Burying Beetles? A Test Case with Nicrophorus Defodiens
Authors: Suswaram M. , Belk M. , Creighton C. 
Published: July 2021

AbstractCommunal breeding is a reproductive system in which more than a single pair of individuals share parental care duties. Burying beetles (genus Nicrophorus) breed on small vertebrate carcasses, which is used as a food source for their young. On larger carcasses, burying beetles will breed communally, forming multiple male-female associations. A significant and costly component of parental investment by burying beetles is the preservation of the carcass with secretions containing immune molecules. Because this immune investment is for the benefit of the offspring, the behavior is a form of social immunity. We test the hypothesis that communal breeding in burying beetles evolved as a mechanism to increase the social immune investment on larger carcasses, which are more difficult to preserve. We used N. defodiens, a communal breeding burying beetle species to test the hypothesis. There were two experimental treatments wherein, the females either bred communally or non-communally. Our results show that the combined immune activity in the secretions were higher in communally breeding pairs than in the immune contribution of single male-female pairs. However, subordinate females were rarely observed on the carcass, and the level of social immune activity of dominant females was lower than females breeding singly. These data suggest that communal breeding in N. defodiens decreases the level of investment in social immunity. Our results demonstrate that the presence of multiple females, which is common under natural conditions, can greatly complicate patterns of social immunity investment in burying beetles.
Complex Mutation Profiles in Mismatch Repair and Ribonucleotide Reductase Mutants Reveal Novel Repair Substrate Specificity of MutS Homolog (MSH) Complexes
Authors: Lamb Natalie A. , Bard Jonathan , Loll-Krippleber Raphael , Brown Grant W. , Surtees Jennifer A. 
Published: July 2021

AbstractDetermining mutation signatures is standard for understanding the etiology of human tumors and informing cancer treatment. Multiple determinants of DNA replication fidelity prevent mutagenesis that leads to carcinogenesis, including the regulation of free deoxyribonucleoside triphosphate (dNTP) pools by ribonucleotide reductase (RNR) and repair of replication errors by the mismatch repair (MMR) system. We identified genetic interactions between rnr1 alleles that elevate dNTP levels and MMR. We then utilized a targeted deep-sequencing approach to determine mutational signatures associated with MMR pathway defects. By combining rnr1 and msh mutations to increase dNTP levels and alter the mutational load, we uncovered previously unreported specificities of Msh2-Msh3 and Msh2-Msh6. Msh2-Msh3 is uniquely able to direct repair of G/C single base deletions in GC runs, while Msh2-Msh6 specifically directs repair of substitutions at G/C dinucleotides. We also identified broader sequence contexts that influence variant profiles in different genetic backgrounds. Finally, we observed that the mutation profiles in double mutants were not necessarily an additive relationship of mutation profiles in single mutants. Our results have implications for interpreting mutation signatures from human tumors, particularly when MMR is defective.
Malignancy and NF-kB signalling strengthen coordination between the expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes
Authors: Perez Marcos Francisco , Sarkies Peter 
Published: July 2021

AbstractMitochondria are ancient endosymbiotic organelles crucial to eukaryotic growth and metabolism. Mammalian mitochondria carry a small genome containing thirteen protein-coding genes with the remaining mitochondrial proteins encoded by the nuclear genome. Little is known about how coordination between the two sets of genes is achieved. Correlation analysis of RNA-seq expression data from large publicly-available datasets is a common method to leverage genetic diversity to infer gene co-expression modules. Here we use this method to investigate nuclear-mitochondrial gene expression coordination. We identify a pitfall in correlation analysis that results from the large variation in the proportion of transcripts from the mitochondrial genome in RNA-seq data. Commonly used normalization techniques based on total read count (such as FPKM or TPM) produce artefactual negative correlations between mitochondrial- and nuclear-encoded transcripts. This also results in artefactual correlations between pairs of nuclear-encoded genes, thus having important consequences for inferring co-expression modules beyond mitochondria. We show that these effects can be overcome by normalizing using the median-ratio normalization (MRN) or trimmed mean of M values (TMM) methods. Using these normalizations, we find only weak and inconsistent correlations between mitochondrial and nuclear-encoded mitochondrial genes in the majority of healthy human tissues from the GTEx database. However, a subset of healthy tissues with high expression of NF-κB show significant coordination supporting a role for NF-κB in retrograde signalling. Contrastingly, most cancer types show robust coordination of nuclear and mitochondrial OXPHOS gene expression, identifying this as a feature of gene regulation in cancer.
Intrinsic Network Activity Reflects the Fluctuating Experience of Tonic Pain
Authors: Deak Bettina , Eggert Thomas , Mayr Astrid , Stankewitz Anne , Filippopulos Filipp , Jahn Pauline , Witkovsky Viktor , Straube Andreas , Schulz Enrico 
Published: July 2021

AbstractAlthough we know sensation is continuous, research on long-lasting and continuously changing stimuli is scarce and the dynamic nature of ongoing cortical processing is largely neglected.In a longitudinal study with 152 fMRI sessions, participants were asked to continuously rate the intensity of applied tonic heat pain for 20 minutes. Using group independent component analysis and dual-regression, we extracted the subjects’ time courses of intrinsic network activity. The relationship between the dynamic fluctuation of network activity with the varying time courses of three pain processing entities was computed: pain intensity, the direction of pain intensity changes and temperature.We were able to dissociate the spatio-temporal patterns of objective (temperature) and subjective (pain intensity/changes of pain intensity) aspects of pain processing in the human brain. We found two somatosensory networks with distinct functions: one network which encodes the small fluctuations in temperature and consists mainly of bilateral SI. A second right-lateralised network that encodes the intensity of the subjective experience of pain consists of SI, SII, the PCC, and the thalamus.We revealed the somatosensory dynamics that build up towards a current subjective percept of pain. The timing suggests a cascade of subsequent processing steps towards the current pain percept.
CRISPR/Cas9-mediated gene disruption of endogenous co-receptors confers broad resistance to HIV-1 in human primary cells and humanized mice
Authors: Li Shasha , Holguin Leo , Burnett John C. 
Published: July 2021

AbstractIn this project, we investigated the CRISPR/Cas9 system for creating HIV resistance by targeting the human CCR5 and CXCR4 genes, which encode cellular co-receptors required for HIV-1 infection. Using a clinically scalable system for transient ex vivo delivery of Cas9/gRNA ribonucleoprotein (RNP) complexes, we demonstrated that CRISPR-mediated disruption of CCR5 and CXCR4 in T-lymphocytes cells significantly reduced surface expression of the co-receptors, thereby establishing resistance to HIV-1 infection by CCR5 (R5)-tropic, CXCR4 (X4)-tropic, and dual (R5/X4)-tropic strains. CRISPR-mediated disruption of the CCR5 alleles in human CD34+ hematopoietic stem and progenitor cells (HSPCs) led to the differentiation of HIV-resistant macrophages. In human CD4+ T cells transplanted into a humanized mouse model, disruption of CXCR4 inhibited replication of X4-tropic HIV-1, thus leading to the virus-mediated enrichment CXCR4-disrupted cells in the peripheral blood and spleen. However, in human CD4+ T cells with both CCR5 and CXCR4 disruption, we observed poor engraftment in bone marrow, although significant changes were not observed in the lung, spleen, or peripheral blood. This study establishes a clinically scalable strategy for the dual knockout of HIV-1 co-receptors as a therapeutic strategy, while also raising caution of disrupting CXCR4, which may abate engraftment of CD4+ T cells in bone marrow.
Proximity-dependent biotinylation to elucidate the interactome of TNK2 non-receptor tyrosine kinase
Authors: Tahir Raiha , Madugundu Anil K. , Udainiya Savita , Cutler Jevon A. , Renuse Santosh , Wang Li , Pearson Nicole A. , Mitchell Chris , Mahajan Nupam , Pandey Akhilesh , Wu Xinyan 
Published: July 2021

ABSTRACTNon-receptor tyrosine kinases represent an important class of signaling molecules which are involved in driving diverse cellular pathways. Although, the large majority have been well-studied in terms of their protein-binding partners, the interactomes of some of the key non-receptor tyrosine kinases such as TNK2 (also known as activated Cdc42-associated kinase 1 or ACK1) have not been systematically investigated. Aberrant expression and hyperphosphorylation of TNK2 has been implicated in a number of cancers. However, the exact proteins and cellular events that mediate phenotypic changes downstream of TNK2 are unclear. Biological systems that employ proximity-dependent biotinylation methods, such as BioID, are being increasingly used to map protein-protein interactions as they provide increased sensitivity in discovering interaction partners. In this study, we employed BioID coupled to the biotinylation site identification technology (BioSITe) method that we recently developed to perform molecular mapping of intracellular proteins associated with TNK2. We also employed stable isotope labeling with amino acids in cell culture (SILAC) to quantitatively explore the interactome of TNK2. By performing a controlled comparative analysis between full-length TNK2 and its truncated counterpart, we were not only able to confidently identify site-level biotinylation of previously well-established TNK2 binders and substrates such as NCK1, NCK2, CTTN, STAT3, but also discover several novel TNK2 interacting partners. We validated TNK2 interaction with one of the novel TNK2 interacting protein, clathrin interactor 1 (CLINT1), using immunoblot analysis. Overall, this work reveals the power of the BioSITe method coupled to BioID and highlights several molecules that warrant further exploration to assess their functional significance in TNK2-mediated signaling.
High-throughput variant detection using a color-mixing strategy
Authors: Xie Nina Guanyi , Zhang Kerou , Song Ping , Li Renqiang , Luo Junfeng , Zhang David Yu 
Published: July 2021

ABSTRACTMany diseases are related to multiple genetic alterations along a single gene. Probing for highly multiple (>10) variants in a single qPCR tube is not possible due to a limited number of fluorescence channels and one variant per channel, so many more tubes are needed. Here, we experimentally validate our novel color-mixing strategy that uses fluorescence combinations as digital color codes to probe multiple variants simultaneously. The color-mixing strategy relies on a simple intra-tube assay that can probe for 15 variants as part of an inter-tube assay that can probe for an exponentially increased number of variants. The color-mixing strategy is achieved using multiplex double-stranded toehold probes modified with fluorophores and quenchers; the probes are designed to be quenched or luminous after binding to wildtype or variant templates. We used the color-mixing strategy to probe for 21 pathogenic mutations in thalassemia and to distinguish between heterozygous and homozygous variants in 6 tubes, with a specificity of 99% and a sensitivity of 94%. To support tuberculosis diagnosis, we used the same strategy to simultaneously probe in Mycobacterium tuberculosis for rifampicin-resistance mutations occurring within one 81-bp region and one 48-bp region in rpoB gene, plus five isoniazid-resistance mutations in inhA and katG genes.
A model of rapid homeostatic plasticity accounts for hidden, long-lasting changes in a neuronal circuit after exposure to high potassium
Authors: Rue Mara C.P. , Alonso Leandro , Marder Eve 
Published: July 2021

AbstractNeural circuits must both function reliably and flexibly adapt to changes in their environment. We studied how both biological neurons and computational models respond to high potassium concentrations. Pyloric neurons of the crab stomatogastric ganglion (STG) initially become quiescent, then recover spiking activity in high potassium saline. The neurons retain this adaptation and recover more rapidly in subsequent high potassium applications, even after hours in control saline. We constructed a novel activity-dependent computational model that qualitatively captures these results. In this model, regulation of conductances is gated on and off depending on how far the neuron is from its target activity. This allows the model neuron to retain a trace of past perturbations even after it returns to its target activity in control conditions. Thus, perturbation, followed by recovery of normal activity, can hide cryptic changes in neuronal properties that are only revealed by subsequent perturbations.
What older adults do in online communities when they co-create and co-destruct value
Authors: Kamalpour Mostafa , Eden Rebekah , Syed Rehan A. , Buys Laurie , Tariq Amina , Watson Jason 
Published: July 2021

Purpose
This study aims to explain the value co-creation and co-destruction practices of older adults in an online community (OC).

Design/methodology/approach
Adopting practice theory and service-dominant logic as a theoretical perspective, this paper examined an OC of older adults by conducting an inductive thematic analysis of the interactions of the participants in the community.

Findings
The analysis revealed older adults engage with three value co-creation plus one value co-destruction practices in the OC including, communal coping practices, happiness creation practices, social capital generation practices and disparaging practices for older adults.

Research limitations/implications
Illustrated in a conceptual model, this study extends previous work evidencing OCs serve as a platform for value co-creation and value co-destruction activities in the context of older adults. Further, it suggests OCs facilitate resilience of older adults through value co-creation practices. Recognition of value co-destruction in OCs is critical as it is detrimental to the resilience of older adults. This study provides the needed foundation to advance knowledge on the use of OCs by older adults and suggests future research directions.

Practical implications
Identifying co-creation and co-destruction practices of older adults in OCs enables service providers (e.g. caregivers) to engage better in online value co-creation practices. Further, the findings of this study address one of the main priorities of service science to investigate the impact of value co-creation on well-being.

Originality/value
Despite the significant engagement of older adults in OCs, there is a lack of enough knowledge in the literature regarding value co-creation and co-destruction practices of older adults in OCs. This study addressed this gap by explaining how older adults co-create and co-destruct value in online spaces.
Gender inequality: determinants and outcomes in Nigeria
Authors: Adeosun Oluyemi Theophilus , Owolabi Kayode Ebenezer 
Published: July 2021

PurposeThis paper aims to shed light on gender inequality in Nigeria exploring new available data. It makes a case for attention to women empowerment and likely economic outcomes. The general objective of the research work is to ascertain the direction of gender inequality and show the pattern of inequality. Also, sectoral trends are obtained by analyzing and examining income inequality in Nigeria.Design/methodology/approachThe paper obtained data from the Living Standard Measurement Survey Wave 3, published 2017 with emphasis on the earnings that accrued to both male and female. The study employed the ordinary least square (OLS) method to show the relationship between the mean income and other parameters such as the sector of employment, marital status and education level. Theil’s entropy index was used to measure the within and between inequality that exist in the economy and across regions and sectors while adopting the overcrowding theory.FindingsThe result shows that gender inequality is more pronounced across the region, location and in some sectors of employment than the others. Geographical area has a higher effect on earnings disparity but is more pronounced among females. Also, the result showed that gender within inequality was high in the regions, education, location, and marital status while a higher level of education contributes to high wages for women. However, married women are more deprived.Originality/valueThis study has further revealed the need to bridge the gap gender inequality has caused in Nigeria, especially related to income, education and geographical location, with a focus on both opportunities and outcomes.
A causal model of functional status among persons with liver cirrhosis from four public hospitals in Thailand
Authors: Maninet Surachai , Aungsuroch Yupin , Jitpanya Chanokporn 
Published: July 2021

PurposeThe purpose of this study is to develop and test the causal relationships between alcohol consumption, social support, illness perception, fatigue and functional status among persons with liver cirrhosis. The hypothesized model was developed based on the theory of unpleasant symptoms.Design/methodology/approachA cross-sectional study was conducted among 400 persons with liver cirrhosis by stratified random sampling. Data were collected at outpatient departments from four public hospitals across three regions in Thailand. Six self-report questionnaires were utilized to collect data from March to August 2020. The developed model was verified via a structural equation modeling analysis.FindingsThe proposed model fit with the empirical data considering from χ2/df = 2.397 (p = 0.061), root mean square error of approximation (RMSEA) = 0.056, comparative fit index (CFI) = 0.985, Tucker–Lewis index (TLI) = 0.981, and standardized root mean square residual (SRMR) = 0.048. The model explained 71.30% of the total variance in functional status. Social support was the most influential factor affecting functional status both directly and indirectly through illness perception. Illness perception had a negative direct effect on functional status and a positive indirect effect on functional status through fatigue. Fatigue had a negative direct effect on functional status. Alcohol consumption was found as the lowest influential factor affecting functional status.Originality/valueThis is the first study that explores the characteristics of functional status among persons with liver cirrhosis comprehensively. A causal relationship among various variables found in this study would shed light as important fundamental data for developing interventions to enhance functional status among this population.
Preparing for market disruption: circuit breakers and discretionary trading halts
Authors: Morton Jennifer , Sacks Russell , Jordan Jenny Ding , Blau Steven , Kelly P. Sean , Pugliese Taylor , Lewis Andrew , Maddox Caitlin Hutchinson 
Published: July 2021

Purpose
This article provides a resource for traders and other market participants by providing an overview of certain automatic circuit breaker mechanisms and discretionary powers that the U.S. Securities and Exchange Commission (SEC), Financial Industry Regulatory Authority (FINRA) and the U.S. president, as applicable, can exercise to pause or stop the trading of individual securities or trading activities across exchanges during extreme market volatility, each of which can cause interruptions to trading activity.

Design/methodology/approach
This article surveys automatic and discretionary mechanisms to halt trading activity under extreme market conditions. In particular, the article examines automatic cross-market circuit breakers, limit up-limit down pauses, the alternative uptick rule, as well as discretionary authority to stop short selling of particular securities and to stop trading across exchanges.

Findings
The article concludes that market participants must be cognizant not only of automatic cross-market circuit breakers, but also several other forms of potential market disruptions that may occur due to increased market volatility during the COVID-19 pandemic and beyond.

Originality/value
By exploring various mechanisms that respond to market disruption, this article provides a valuable resource for traders and other market participants looking to identify and respond to potential interruptions to their trading activity.