bluuebunny/crossref_metadata_2025_split huggingface dataset:
The protective effect of aspirin in colorectal carcinogenesis: a multiscale computational study from mutant evolution to age incidence curves
Authors: Wang Yifan , Boland C. Richard , Goel Ajay , Wodarz Dominik , Komarova Natalia L. 
Published: May 2021

AbstractAspirin intake has been shown to lead to significant protection against colorectal cancer, e.g. with an up to two-fold reduction in colorectal adenoma incidence rates at higher doses. The mechanisms contributing to protection are not yet fully understood. While aspirin is an anti-inflammatory drug and can thus influence the tumor microenvironment, in vitro and in vivo experiments have recently shown that aspirin can also have a direct effect on cellular kinetics and fitness. It reduces the rate of tumor cell division and increases the rate of cell death. The question arises whether such changes in cellular fitness are sufficient to significantly contribute to the epidemiologically observed protection. To investigate this, we constructed a class of mathematical models of in vivo evolution of advanced adenomas, parameterized it with available estimates, and calculated population level incidence. Fitting the predictions to age incidence data revealed that only a model that included colonic crypt competition can account for the observed age-incidence curve. This model was then used to predict modified incidence patterns if cellular kinetics were altered as a result of aspirin treatment. We found that changes in cellular fitness that were within the experimentally observed ranges could reduce advanced adenoma incidence by a sufficient amount to account for age incidence data in aspirin-treated patient cohorts. While the mechanisms that contribute to the protective effect of aspirin are likely complex and multi-factorial, our study demonstrates that direct aspirin-induced changes of tumor cell fitness can significantly contribute to epidemiologically observed reduced incidence patterns.
A fluorescence-based genetic screen reveals diverse mechanisms silencing small RNA signaling inE. coli
Authors: Chen Jiandong , To Leann , de Mets Francois , Luo Xing , Majdalani Nadim , Tai Chin-Hsien , Gottesman Susan 
Published: May 2021

AbstractAs key players of gene regulation in many bacteria, small regulatory RNAs (sRNAs) associated with the RNA chaperone Hfq shape numerous phenotypic traits, including metabolism, stress response and adaptation as well as virulence. sRNAs can alter target mRNA translation and stability via base pairing. sRNA synthesis is generally under tight transcriptional regulation, but other levels of regulation of sRNA signaling are less well understood. Here we used a fluorescence-based functional screen to identify new regulators that can quench sRNA signaling of the iron-responsive sRNA RyhB inE. coli. The identified regulators fell into two classes, general regulators (affecting signaling by many sRNAs) and RyhB-specific regulators; we focused on the specific ones here. General regulators include three Hfq-interacting sRNAs, CyaR, ChiX and McaS, previously found to act through Hfq competition, RNase T, a 3′-5′ exonuclease not previously implicated in sRNA degradation, and YhbS, a putative GCN5-related N-acetyltransferase (GNAT). Two new specific regulators were identified. AspX, a novel 3′end-derived small RNA, specifically represses RyhB signaling via an RNA sponging mechanism. YicC, a previously uncharacterized but widely conserved protein, triggers rapid RyhB degradation via collaboration with the exoribonuclease PNPase. These findings greatly expand our knowledge of regulation of bacterial sRNA signaling and suggest complex regulatory networks for controlling iron homeostasis in bacteria. The fluorescence-based genetic screen system described here is a powerful tool expected to accelerate the discovery of novel regulators of sRNA signaling in many bacteria.SignificanceThe ability to promptly switch genes on and off allows bacteria to adapt rapidly to changing environments for better survival. Many sRNAs, including RyhB, a sRNA made in response to iron starvation, are important switches in bacteria. We discovered new factors that can keep the sRNA switch off by using a facile genetic screen platform. These new factors include a new RNA sponge and an adaptor protein for a ribonuclease, providing new perspectives on controlling sRNA signaling in bacteria.
Set4 coordinates the activity of histone deacetylases and regulates stress-responsive gene expression within subtelomeric regions in yeast
Authors: Jethmalani Yogita , Tran Khoa , Jaiswal Deepika , Jezek Meagan , Ramos Mark , Amos Shandon , Garcia Eric Joshua , Negesse Maraki Y. , Sun Winny , Park DoHwan , Green Erin M. 
Published: May 2021

AbstractThe yeast chromatin protein Set4 is a member of the Set3-subfamily of SET domain proteins which play critical roles in the regulation of gene expression in diverse developmental and environmental contexts, although they appear to lack methyltransferase activity. The molecular functions of Set4 are relatively unexplored, likely due to its low abundance in standard growth conditions. We previously reported that Set4 promotes survival during oxidative stress and regulates expression of stress response genes via stress-dependent chromatin localization. In this study, global gene expression analysis and investigation of histone modification status has revealed a role for Set4 in maintaining gene repressive mechanisms within yeast subtelomeres under both normal and stress conditions. We show that Set4 works in a partially overlapping pathway to the SIR complex and the histone deacetylase Rpd3 to maintain proper levels of histone acetylation and expression of stress response genes encoded in subtelomeres. This role for Set4 is particularly critical for cells under hypoxic conditions, and the loss of Set4 decreases cell fitness and cell wall integrity in hypoxia. These findings uncover a new regulator of subtelomeric chromatin that is key to stress defense pathways and demonstrate a function for yeast Set4 in regulating repressive, heterochromatin-like environments.
Inferring the COVID-19 infection fatality rate in the community-dwelling population: a simple Bayesian evidence synthesis of seroprevalence study data and imprecise mortality data
Authors: Campbell Harlan , Gustafson Paul 
Published: May 2021

ABSTRACTEstimating the COVID-19 infection fatality rate (IFR) has proven to be particularly challenging –and rather controversial– due to the fact that both the data on deaths and the data on the number of individuals infected are subject to many different biases. We consider a Bayesian evidence synthesis approach which, while simple enough for researchers to understand and use, accounts for many important sources of uncertainty inherent in both the seroprevalence and mortality data. With the understanding that the results of one’s evidence synthesis analysis may be largely driven by which studies are included and which are excluded, we conduct two separate parallel analyses based on two lists of eligible studies obtained from two different research teams. The results from both analyses are rather similar. With the first analysis, we estimate the COVID-19 IFR to be 0.31% (95% credible interval of (0.16%, 0.53%)) for a typical community-dwelling population where 9% of the population is aged over 65 years and where the gross-domestic product at purchasing-power parity (GDP at PPP) per capita is $17.8k (the approximate worldwide average). With the second analysis, we obtain 0.32% (95% credible interval of (0.19%, 0.47%)). Our results suggest that, as one might expect, lower IFRs are associated with younger populations (and may also be associated with wealthier populations). For a typical community-dwelling population with the age and wealth of the United States we obtain IFR estimates of 0.43% and 0.41%; and with the age and wealth of the European Union, we obtain IFR estimates of 0.67% and 0.51%.Above all, what’s needed is humility in the face of an intricately evolving body of evidence. The pandemic could well drift or shift into something that defies our best efforts to model and characterize it.Siddhartha Mukherjee,The New YorkerFebruary 22, 2021
Construction and Validation of the Ohio Children’s Opportunity Index
Authors: Fareed Naleef , Singh Priti , Jonnalagadda Pallavi , Swoboda Christine M. , Odden Colin , Doogan Nathan 
Published: May 2021

ABSTRACTObjectiveTo describe the development of an area-level measure of children’s opportunity, the Ohio Children’s Opportunity Index (OCOI).Data Sources/Study SettingSecondary data were collected from US census based-American Community Survey (ACS), US Environmental Protection Agency, US Housing and Urban Development, Ohio Vital Statistics, US Department of Agriculture-Economic Research Service, Ohio State University Center for Urban and Regional Analysis, Ohio Incident Based Reporting System, IPUMS National Historical Geographic Information System, and Ohio Department of Medicaid.Study DesignOCOI domains were selected based on existing literature, which included family stability, infant health, children’s health, access, education, housing, environment and criminal justice domains. The composite index was developed using an equal weighting approach. Validation analyses were conducted between OCOI and health and race-related outcomes.Data Collection/Extraction MethodsData were aggregated at the census tract level.Principal FindingsComposite OCOI scores ranged from 0-100 with an average value of 74.82 (SD, 17.00), was negatively skewed. Census tracts in the major metropolitan cities across Ohio represented 76% of the total census tracts in the least advantaged OCOI septile. OCOI served as a significant predictor of health and race-related outcomes. The average life expectancy at birth of children born in the most advantaged septile was approximately nine years more than those born in the least advantaged septile. Increases in OCOI were associated with decreases in proportion of Black (48 points lower in the most advantaged vs least advantaged septile), p<0.001) and Minority populations (54 points lower in most advantaged vs least advantaged septile, p<0.001).ConclusionAs the first opportunity index developed for children in Ohio, the OCOI is a valuable resource for policy reform, especially related to health equity. Health care providers can use it to obtain more holistic views on their patients and implement interventions that can tackle barriers to childhood development.
The cerebellum as a moderator of negative bias of facial expression processing in depressive patients
Authors: Nakamura Anna , Yomogida Yukihito , Ota Miho , Matsuo Junko , Ishida Ikki , Hidese Shinsuke , Kunugi Hiroshi 
Published: May 2021

AbstractBackgroundNegative bias—a mood-congruent bias in emotion processing—is an important aspect of major depressive disorder (MDD), and such a bias in facial expression recognition has a significant effect on patients’ social lives. Neuroscience research shows abnormal activity in emotion-processing systems regarding facial expressions in MDD. However, the neural basis of negative bias in facial expression processing has not been explored directly.MethodsSixteen patients with MDD and twenty-three healthy controls (HC) who underwent an fMRI scan during an explicit facial emotion task with happy to sad faces were selected. We identified brain areas in which the MDD and HC groups showed different correlations between the behavioral negative bias scores and functional activities.ResultsBehavioral data confirmed the existence of a higher negative bias in the MDD group. Regarding the relationship with neural activity, higher activity of happy faces in the posterior cerebellum was related to a higher negative bias in the MDD group, but lower negative bias in the HC group.LimitationsThe sample size was small, and the possible effects of medication were not controlled for in this study.ConclusionsWe confirmed a negative bias in the recognition of facial expressions in patients with MDD. fMRI data suggest the cerebellum as a moderator of facial emotion processing, which biases the recognition of facial expressions toward their own mood.
KAHRP dynamically relocalizes to remodeled actin junctions and associates with knob spirals in P. falciparum-infected erythrocytes
Authors: Sanchez Cecilia P. , Patra Pintu , Chang Shih-Ying , Karathanasis Christos , Hanebutte Lukas , Kilian Nicole , Cyrklaff Marek , Heilemann Mike , Schwarz Ulrich S. , Kudryashev Mikhail , Lanzer Michael 
Published: May 2021

SummaryThe knob-associated histidine-rich protein (KAHRP) plays a pivotal role in the pathophysiology of Plasmodium falciparum malaria by forming membrane protrusions in infected erythrocytes, which anchor parasite-encoded adhesins to the membrane skeleton. The resulting sequestration of parasitized erythrocytes in the microvasculature leads to severe disease. Despite KAHRP being an important virulence factor, its physical location within the membrane skeleton is still debated, as is its function in knob formation. Here, we show by super-resolution microscopy that KAHRP initially associates with various skeletal components, including ankyrin bridges, but eventually co-localizes with remnant actin junctions. We further present a 35Å map of the spiral scaffold underlying knobs and show that a KAHRP-targeting nanoprobe binds close to the spiral scaffold. Single-molecule localization microscopy detected ∼60 KAHRP molecules per knob. We propose a dynamic model of KAHRP organization and a function of KAHRP in attaching other factors to the spiral scaffold.
The repeat region of the circumsporozoite protein is an elastic linear spring with a functional role in Plasmodium sporozoite motility
Authors: Balaban Amanda E. , Kanatani Sachie , Mitra Jaba , Gregory Jason , Vartak Natasha , Sinnis-Bourozikas Ariadne , Frischknecht Fredrich , Ha Taekjip , Sinnis Photini 
Published: May 2021

AbstractThe circumsporozoite protein (CSP) forms a dense coat on the surface of the sporozoite, the infective stage of the malaria parasite. The central repeat region of CSP is a critical component of the only licensed malaria vaccine yet little is known about its structure or function. We found that sporozoite mutants with severely truncated or scrambled repeats have impaired motility due to altered adhesion site formation and dynamics, suggesting that the CSP repeats provide a cohesive environment in which adhesion sites can form. We hypothesized that biophysical properties of the repeats are important in this role and interrogated this using single-molecule fluorescence-force spectroscopy. We show that the repeats are a stiff, linear spring with elastic properties, dependent upon length and lost when the repeats are scrambled. These data are the first evidence that the CSP repeat region serves a functional role during infection and motility, likely mediated through its biophysical properties.SummaryNo clear function of the central repeat region of the malaria circumsporozoite protein has been described to date, despite its central role in the only licensed malaria vaccine. Here we use mutational analysis and single-molecule fluorescence-force spectroscopy to describe the structural properties and determine the function of this conserved region and important vaccine target.HighlightsThe CSP repeats have properties of a linear springScrambling or large truncations of the repeats leads to defects in sporozoite motilityMotility defects are attributed to abnormal formation of adhesion sites
Polymerization of C9 enhances bacterial cell envelope damage and killing by membrane attack complex pores
Authors: Doorduijn Dennis J. , Heesterbeek Dani A.C. , Ruyken Maartje , de Haas Carla J.C. , Stapels Daphne A.C. , Aerts Piet C. , Rooijakkers Suzan H. M. , Bardoel Bart W. 
Published: May 2021

AbstractComplement proteins can form Membrane Attack Complex (MAC) pores that directly kill Gram-negative bacteria. MAC pores assemble by stepwise binding of C5b, C6, C7, C8 and finally C9, which can polymerize into a transmembrane ring of up to 18 C9 monomers. It is still unclear if the assembly of a polymeric-C9 ring is necessary to sufficiently damage the bacterial cell envelope to kill bacteria, because a robust way to specifically prevent polymerization of C9 has been lacking. In this paper, polymerization of C9 was prevented without affecting the binding of C9 to C5b-8 by locking the first transmembrane helix domain of C9. We show that polymerization of C9 strongly enhanced bacterial cell envelope damage and killing by MAC pores for severalEscherichia coliandKlebsiellastrains. Moreover, we show that polymerization of C9 is impaired on complement-resistantE. colistrains that survive killing by MAC pores. Altogether, these insights are important to understand how MAC pores kill bacteria and how bacterial pathogens can resist MAC-dependent killing.
Uncoupling of Chromatin Assembly from DNA Replication in Sciara Reveals a Domain of Postreplicative Immature Chromatin
Authors: Urnov Fyodor D. , Scheer Ulrich , Zentgraf Hanswalter , Smith Heidi S. , Gerbi Susan A. 
Published: May 2021

ABSTRACTDNA replication in dividing eukaryotic cells imposes a requirement for the faithful recreation on the newly synthesized chromatids of the nucleoprotein architecture of parent chromosomes. Practically nothing is known about the structure of postreplicative immature chromatin—a very short-lived entity (< 30 min.). We report here the unexpected discovery that during DNA amplification of locus II/9A in salivary gland polytene chromosomes of the fungus fly Sciara coprophila, DNA replication fork passage is uncoupled from postreplicative chromatin assembly; this enables visualization and analysis of chromatin fibers disassembled by DNA replication. We used electron microscopy to visualize a wealth of low nucleosome density immature chromatin fibers in preparations of Sciara chromatin from amplification-stage tissue. Remarkably, as gauged by high sensitivity to micrococcal nuclease and an unusually short length of DNA associated with each histone octamer, we found that locus II/9A which undergoes amplification and is replicated once every 4-6 hrs.—but not the bulk genome or a replicatively quiescent DNA stretch—was maintained in such an ummature fiber for ca. 24 hrs. Following amplification, locus II/9A assumed conventional chromatin organization, indicating that the epigenetic mark targeting nascent DNA to the chromatin assembly machinery is stable for several hours. We propose that this very unusual prolonged maintenance of a segment of the genome in immature chromatin facilitates access by the basal transcriptional machinery to the amplified DNA, and thus is an evolutionary adaptation to the demand for high transcription from genes that reside in the amplified loci.
Students' perception of learning from entrepreneurship education programs and entrepreneurial intention in Latin America
Authors: Lopez Tatiana , Alvarez Claudia , Martins Izaias , Perez Juan P. , Románn-Calderón Juan Pablo 
Published: May 2021

PurposeDrawing on entrepreneurship education and entrepreneurial intention literature, this paper develops and tests a model that aims to explain the relationship between students' perception of learning from entrepreneurship education programs (EEP), the theory of planned behavior and entrepreneurial intention across Latin American countries.Design/methodology/approachThis study uses data from the Global University Entrepreneurship Spirit Student’s Survey (GUESSS) project 2018 for 11 Latin American countries. Structural equation modeling is used to validate the theoretical model; this offers advantages over traditional multivariate techniques in evaluating measurement errors, estimation of latent variables and specification of models.FindingsThe main results suggest that a positive perception of learning from EEP is related to the antecedents of entrepreneurial intention. Moreover, attitude toward entrepreneurial behavior and perceived behavior control positively influences entrepreneurial intention across Latin American undergraduate students. The findings contribute to a better understanding of the role of EEP in terms of the antecedents of the intention and, in addition, provide evidence to the theory of planned behavior from a large sample in an emerging region.Originality/valueThe theory of planned behavior is one of the most important theoretical frameworks to explain entrepreneurial intention. However, in Latin American countries, quality research is hindered by the lack of data and valid measures. Therefore, the paper adds value by looking at the perception of learning from EEP and its relationship with the antecedents of intention. Likewise, it validates the dimensions of the theory of planned behavior and its relationship to entrepreneurial intention, considering a broad sample of university students in Latin America.
Data cleaning issues in class imbalanced datasets: instance selection and missing values imputation for one-class classifiers
Authors: Wang Zhenyuan , Tsai Chih-Fong , Lin Wei-Chao 
Published: May 2021

PurposeClass imbalance learning, which exists in many domain problem datasets, is an important research topic in data mining and machine learning. One-class classification techniques, which aim to identify anomalies as the minority class from the normal data as the majority class, are one representative solution for class imbalanced datasets. Since one-class classifiers are trained using only normal data to create a decision boundary for later anomaly detection, the quality of the training set, i.e. the majority class, is one key factor that affects the performance of one-class classifiers.Design/methodology/approachIn this paper, we focus on two data cleaning or preprocessing methods to address class imbalanced datasets. The first method examines whether performing instance selection to remove some noisy data from the majority class can improve the performance of one-class classifiers. The second method combines instance selection and missing value imputation, where the latter is used to handle incomplete datasets that contain missing values.FindingsThe experimental results are based on 44 class imbalanced datasets; three instance selection algorithms, including IB3, DROP3 and the GA, the CART decision tree for missing value imputation, and three one-class classifiers, which include OCSVM, IFOREST and LOF, show that if the instance selection algorithm is carefully chosen, performing this step could improve the quality of the training data, which makes one-class classifiers outperform the baselines without instance selection. Moreover, when class imbalanced datasets contain some missing values, combining missing value imputation and instance selection, regardless of which step is first performed, can maintain similar data quality as datasets without missing values.Originality/valueThe novelty of this paper is to investigate the effect of performing instance selection on the performance of one-class classifiers, which has never been done before. Moreover, this study is the first attempt to consider the scenario of missing values that exist in the training set for training one-class classifiers. In this case, performing missing value imputation and instance selection with different orders are compared.