bluuebunny/crossref_metadata_2025_split huggingface dataset:
Examining the Unit Costs of COVID-19 Vaccine Delivery in Kenya
Authors: Orangi Stacey , Kairu Angela , Ngatia Anthony , Ojal John , Barasa Edwine 
Published: November 2021

ABSTRACTIntroductionVaccines are considered the path out of the COVID-19 pandemic. The government of Kenya is implementing a phased strategy to vaccinate the Kenyan population, initially targeting populations at high risk of severe disease and infection. We estimated the financial and economic unit costs of procuring and delivering the COVID-19 vaccine in Kenya across various vaccination strategies.MethodsWe used an activity-based costing approach to estimate the incremental costs of COVID-19 vaccine delivery, from a health systems perspective. Document reviews and key informant interviews (n=12) were done to inform the activities, assumptions and the resources required. Unit prices were derived from document reviews or from market prices. Both financial and economic vaccine procurement costs per person vaccinated with 2-doses, and the vaccine delivery costs per person vaccinated with 2-doses were estimated and reported in 2021USD.ResultsThe financial costs of vaccine procurement per person vaccinated with 2-doses ranged from $2.89-$13.09 in the 30% and 100% coverage levels respectively, however, the economic cost was $17.34 across all strategies. Financial vaccine delivery costs per person vaccinated with 2-doses, ranged from $4.28-$3.29 in the 30% and 100% coverage strategies: While the economic delivery costs were two to three times higher than the financial costs. The total procurement and delivery costs per person vaccinated with 2-doses ranged from $7.34-$16.47 for the financial costs and $29.7-$24.68 for the economic costs for the 30% and 100% coverage respectively. With the exception of procurement costs, the main cost driver of financial and economic delivery costs was supply chain costs (47-59%) and advocacy, communication and social mobilization (29-35%) respectively.ConclusionThis analysis presents cost estimates that can be used to inform local policy and may further inform parameters used in cost-effectiveness models. The results could potentially be adapted and adjusted to country-specific assumptions to enhance applicability in similar low-and middle-income settings.
Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19
Authors: Nln Ilona , Fernandez-Ruiz Ruth , Wampler Muskardin Theresa L. , Paredes Jacqueline L. , Blazer Ashira D. , Tuminello Stephanie , Attur Mukundan , Iturrate Eduardo , Petrilli Christopher M. , Abramson Steven B. , Chakravarti Aravinda , Niewold Timothy B. 
Published: November 2021

AbstractType I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity.BackgroundWe find that a number of IFN pathway lupus risk alleles significantly impact mortality following COVID-19 infection. These data support the idea that type I IFN pathway risk alleles for autoimmune disease may persist in high frequency in modern human populations due to a benefit in our defense against viral infections.Translational SignificanceWe develop multivariate prediction models which combine genetics and known biomarkers of severity to result in greatly improved prediction of mortality in acute COVID-19. The specific associated alleles provide some clues about key points in our defense against COVID-19.
Polyamines and eIF5A hypusination facilitate SREBP2 translation and cholesterol synthesis to enhance enterovirus attachment and infection
Authors: Firpo Mason R. , Petite Marine J. , LoMascolo Natalie J. , Shah Priya S. , Mounce Bryan C. 
Published: November 2021

AbstractMetabolism is key to cellular processes that underlie the ability of a virus to productively infect. Polyamines are small metabolites vital for many host cell processes including proliferation, transcription, and translation. Polyamine depletion also inhibits virus infection via diverse mechanisms, including inhibiting polymerase activity and viral translation. We showed that Coxsackievirus B3 (CVB3) attachment requires polyamines; however, the mechanism was unknown. Here, we report polyamines’ involvement in translation, through a process called hypusination, promotes expression of cholesterol synthesis genes by supporting SREBP2 translation, the master transcriptional regulator of cholesterol synthesis genes. Measuring bulk transcription, we found polyamines support expression of cholesterol synthesis genes, regulated by SREBP2. Polyamine depletion inhibits CVB3 by depleting cellular cholesterol. Exogenous cholesterol rescues CVB3 attachment, and mutant CVB3 resistant to polyamine depletion exhibits resistance to cholesterol perturbation. This study provides a novel link between polyamine and cholesterol homeostasis, a mechanism through which polyamines impact CVB3 infection.
MutationalPatterns: The one stop shop for the analysis of mutational processes
Authors: Manders Freek , Brandsma Arianne M. , de Kanter Jurrian , Verheul Mark , Oka Rurika , van Roosmalen Markus J. , van der Roest Bastiaan , van Hoeck Arne , Cuppen Edwin , van Boxtel Ruben 
Published: November 2021

AbstractBackgroundThe collective of somatic mutations in a genome represents a record of mutational processes that have been operative in a cell. These processes can be investigated by extracting relevant mutational patterns from sequencing data.ResultsHere, we present the next version of MutationalPatterns, an R/Bioconductor package, which allows in-depth mutational analysis of catalogues of single and double base substitutions as well as small insertions and deletions. Major features of the package include the possibility to perform regional mutation spectra analyses and the possibility to detect strand asymmetry phenomena, such as lesion segregation. On top of this, the package also contains functions to determine how likely it is that a signature can cause damaging mutations (i.e., mutations that affect protein function). This updated package supports stricter signature refitting on known signatures in order to prevent overfitting. Using simulated mutation matrices containing varied signature contributions, we showed that reliable refitting can be achieved even when only 50 mutations are present per signature. Additionally, we incorporated bootstrapped signature refitting to assess the robustness of the signature analyses. Finally, we applied the package on genome mutation data of cell lines in which we deleted specific DNA repair processes and on large cancer datasets, to show how the package can be used to generate novel biological insights.ConclusionsThis novel version of MutationalPatterns allows for more comprehensive analyses and visualization of mutational patterns in order to study the underlying processes. Ultimately, in-depth mutational analyses may contribute to improved biological insights in mechanisms of mutation accumulation as well as aid cancer diagnostics. MutationalPatterns is freely available at http://bioconductor.org/packages/MutationalPatterns.
Bacterial growth in multicellular aggregates leads to the emergence of complex lifecycles
Authors: Schwartzman Julia A , Ebrahimi Ali , Chadwick Grayson , Sato Yuya , Orphan Victoria , Cordero Otto X 
Published: November 2021

ABSTRACTIn response to environmental stresses such as starvation, many bacteria facultatively aggregate into multicellular structures that can attain new metabolic functions and behaviors. Despite the ubiquity and relevance of this form of collective behavior, we lack an understanding of how the spatiotemporal dynamics of aggregate development emerge from cellular physiology. Here, we show that the coupling between growth and spatial gradient formation leads to the emergence of a complex lifecycle, akin to those known for multicellular bacteria. Under otherwise carbon-limited growth conditions, the marine bacterium Vibrio splendidus 12B01 forms multicellular groups to collectively harvest carbon from the brown-algal polysaccharide alginate. This is achieved during growth on dissolved alginate polymer through formation of spherical, clonal clusters of cells that grow up to 40 µm in radius. Clusters develop striking spatial patterning as they grow due to phenotypic differentiation of sub-populations into a ‘shell’ of static cells surrounding a motile ‘core’. Combining in situ measurements of cell physiology with transcriptomics, we show that shell cells express adhesive type IV pili, while motile core cells express carbon storage granules. The emergence of shell and core phenotypes is cued by opposing gradients of carbon and nitrogen that form within cell clusters due to local metabolic activity. Eventually, the shell ruptures, releasing the carbon-storing core, and we show that carbon-storing cells more readily propagate on alginate than non-carbon storing cells. We propose that phenotypic differentiation promotes the resilience of 12B01 groups by enabling clonal groups to grow larger and propagate more effectively. Phenotypic differentiation may be a widespread, but overlooked, strategy among bacteria to enhance resilience in the context of resource limitation.
Reactivation of Epstein Barr Virus from Latency Involves Increased RNA Polymerase Activity at CTCF Binding Sites on The Viral Genome
Authors: Dunn Laura E. M. , Lu Fang , Su Chenhe , Lieberman Paul M. , Baines Joel D. 
Published: November 2021

AbstractThe ability of Epstein-Barr Virus (EBV) to switch between latent and lytic infection is key to its long-term persistence, yet the molecular mechanisms behind this switch remain unclear. To investigate transcriptional events during the latent to lytic switch we utilized Precision nuclear Run On followed by deep Sequencing (PRO-Seq) to map cellular RNA polymerase (Pol) activity to single-nucleotide resolution on the host and EBV genome in three different models of EBV latency and reactivation. In latently infected Mutu I Burkitt Lymphoma (BL) cells, Pol activity was enriched at the Qp promoter, the EBER region and the BHLF1/LF3 transcripts. Upon reactivation with phorbol ester and sodium butyrate, early phase Pol activity occurred bidirectionally at CTCF sites within the LMP-2A, EBER-1 and RPMS1 loci. PRO-Seq analysis of Akata cells reactivated from latency with anti-IgG and a lymphoblastoid cell-line (LCL) reactivated with small molecule C60 showed a similar pattern of early bidirectional transcription initiating around CTCF binding sites, although the specific CTCF sites and viral genes were different for each latency model. The functional importance of CTCF binding, transcription and reactivation was confirmed using an EBV mutant lacking the LMP-2A CTCF binding site. This virus was unable to reactivate and had disrupted Pol activity at multiple CTCF binding sites relative to WT virus. Overall, these data suggest that CTCF regulates the viral early transcripts during reactivation from latency. These activities likely help maintain the accessibility of the viral genome to initiate productive replication.Author summaryThe ability of EBV to switch between latent and lytic infection is key to its long-term persistence in memory B-cells and its ability to persist in proliferating cells is strongly linked to oncogenesis. During latency, most viral genes are epigenetically silenced, and the virus must overcome this repression to reactivate lytic replication. Reactivation occurs once the immediate early (IE) EBV lytic genes are expressed. However, the molecular mechanisms behind the switch from the latent transcriptional program to begin transcription of the IE genes remain unknown. In this study, we mapped RNA polymerase (Pol) positioning and activity during latency and reactivation. Unexpectedly, Pol activity was not enriched at the IE genes immediately after reactivation but accumulated at distinct regions characteristic of transcription initiation on the EBV genome previously shown to be associated with CTCF. We propose that CTCF binding at these regions retains Pol to maintain a stable latent chromosome conformation and a rapid response to various reactivation signals.
Quorum sensing signal autoinducer-2 inhibits sporulation ofBacillusby interacting with RapC and functions across species
Authors: Xiong Qin , Zhang Huihui , Shu Xia , Sun Xiting , Feng Haichao , Xu Zhihui , Kovács Ákos T. , Liu Yunpeng , Zhang Ruifu 
Published: November 2021

AbstractCollective behavior of bacteria is regulated by quorum sensing (QS). Bacterial cells sense the density of the population and induce corresponding traits and developmental processes. Autoinducer-2 (AI-2) is a common QS signal that regulates behavior of both Gram-positive and Gram-negative bacteria. In spite of the plethora of processes described to be influenced by AI-2 in diverse Gram-negative bacteria, the AI-2-regulated processes inBacilliare relatively unexplored. Previously, we demonstrated that AI-2 regulates root colonization ofBacillus velezensisSQR9, a well-studied plant beneficial rhizobacterium. Here, we describe a novel function for AI-2 inB. velezensisSQR9 related to development of dormant spores. AI-2 inhibited the initiation of spore development throught the phosphatase RapC and the DNA binding regulator ComA. Using mutant strains and protein-protein interaction studies, we demonstrate that AI-2 interacts with RapC to stimulate its binding to ComA and therefore inactive ComA. We further demonstrate that ComA is essential for Spo0A-regulated sporulation inB. velezensisSQR9. Finally, the AI-2 molecule could be shared cross species for inhibitingBacillussporulation. Our study revealed a novel function and regulation mechanism of AI-2 in sporulation inhibition ofBacillithat overall suggests sporulation to be a population-level decision process inBacillirather than just a individual cell behavior.Author summaryQuorum sensing (QS) regulates many bacterial social behavior. Bacteria cells could moniter and respond cell density by sensing the self produced QS signals. While most QS signals are unique for either Gram-positive or Gram-negative bacteria, autoinducer-2 (AI-2) is a QS signal that could produced by both bacteria groups. However, knowledge of the mechanism of AI-2 affecting bacterial behavior is poorly understood. Here, we found AI-2 inhibiteBacillus velezensisSQR9 sporulation, a generally known bacterial individual behavior. We further revealed the mechanism of AI-2 influencing sporulation ofB. velezensisSQR9 was dependent on RapC and ComA. AI-2 interacts with RapC to stimulate its binding to ComA and therefore inactive ComA, and then inhibited the Spo0A-regulated sporulation. Interestingly, we showB. velezensisSQR9 could also sense the AI-2 produced by other bacteria and reduce their own sporulation. Taken together we discovered the novel function of AI-2 in sporulation, which will expand the significance of QS signal that they regulate not only social behavior but also individual behavior of bacteria.
Cholesterol and sphingomyelin are critical for Fcγ receptor-mediated phagocytosis of Cryptococcus neoformans by macrophages
Authors: Bryan Arielle M. , You Jeehyun Karen , Li Guangtao , Kim JiHyun , Singh Ashutosh , Morstein Johannes , Trauner Dirk , Pereira de Sá Nívea , Normile Tyler G. , Farnoud Amir M. , London Erwin , Del Poeta Maurizio 
Published: November 2021

AbstractCryptococcus neoformans is a fungal pathogen that causes life-threatening meningoencephalitis in lymphopenic patients. Pulmonary macrophages comprise the first line of host defense upon inhalation of fungal spores, whereby macrophages either aid in clearance or serve as a niche for its dissemination. Given that macrophages play a key role in the outcome of a cryptococcal infection, it is crucial to understand factors that mediate phagocytosis of C. neoformans. Since lipid rafts (high order plasma membrane domains enriched in cholesterol and sphingomyelin) have been implicated in facilitating phagocytosis, we evaluated whether these ordered domains govern macrophages’ ability to phagocytose C. neoformans. We found that cholesterol or sphingomyelin depletion resulted in significantly deficient IgG-mediated phagocytosis of the fungus. Moreover, repletion of macrophage cells with a raft-promoting sterol (7-dehydrocholesterol) rescued this phagocytic deficiency while a raft-inhibiting sterol (coprostanol) significantly decreased IgG-mediated phagocytosis of C. neoformans. Using a photoswitchable sphingomyelin (AzoSM), we observed that the raft-promoting conformation (trans-AzoSM) resulted in efficient phagocytosis whereas raft-inhibiting conformation (cis-AzoSM) significantly blunted phagocytosis in a reversible manner. We observed that the effect on phagocytosis may be mediated by facilitating Fcγ receptor (FcγR) function, whereby IgG immune complexes cross-link to FcγRIII, resulting in tyrosine phosphorylation of FcR γ-subunit (FcRγ), an important accessory protein in the FcγR signaling cascade. Correspondingly, cholesterol or sphingomyelin depletion resulted in decreased FcRγ phosphorylation. Repletion with 7-dehydrocholesterol restored phosphorylation, whereas repletion with coprostanol showed FcRγ phosphorylation comparable to unstimulated cells. Together, these data suggest that lipid rafts are critical for facilitating FcγRIII-mediated phagocytosis of C. neoformans.
Implications of tax audit risk, consequences, aggressive behavior and ethics for compliance
Authors: Chan Siew H. , Song Qian 
Published: November 2021

PurposeThis study investigates whether consideration of future consequences (CFC), Machiavellianism (MACH) and the perceived role of ethics and social responsibility (PRESOR) enhance understanding of the impact of tax audit risk on compliance.Design/methodology/approachA between-subjects experiment is conducted to test the hypotheses. A hypothetical tax audit case (or lack thereof) is used to create a high (low) perceived tax audit risk. The usable responses of 144 participants representing the general taxpayer population are analyzed.FindingsThe results suggest that taxpayers with lower CFC, MACH or PRESOR scores are more compliant when tax audit risk is high than low. In contrast, taxpayers with higher CFC, MACH or PRESOR scores are indifferent toward high or low tax audit risk.Research limitations/implicationsResearch can elicit consideration of future consequences of being detected for taxpayers with lower CFC scores to increase compliance. Additionally, increased saliency of tax audit risk and detection of noncompliance in a tax audit can enhance the compliance of taxpayers with lower MACH scores. Dissemination of information via social media on the value of ethical and social responsibility of compliance can also increase the compliance of taxpayers with higher PRESOR scores.Practical implicationsThis study helps researchers and the tax authority better understand the complexities of compliance and the ethical dilemmas that taxpayers face, especially when a considerable amount of cash income is involved. To deter underreporting of cash income, the tax authority can use social media to explain how data analytics tools can facilitate the analysis and integration of multiple sources of a taxpayer’s income and expenses.Originality/valuePrior studies present participants with objective tax audit rates, such as 5, 25 and 30 (Culliset al., 2006; Maciejovskyet al., 2007; Trivediet al., 2003) or 50% (Maciejovskyet al., 2012) to investigate tax compliance. However, the actual tax audit rate is very low (about 1%) due to the limited resources of the tax authority (Alm and Torgler, 2011). To attenuate perceptions of unrealistic tax audit rates, this study operationalizes high (low) tax audit risk via a hypothetical tax audit case (or lack thereof) to examine the impact of tax audit risk on compliance.
Private tutoring in Bangladesh: evolution, expansion, and policy responses
Authors: Alam Md. Bayezid , Zhu Zhiyong 
Published: November 2021

PurposeThis study explores the development trajectory of private tutoring in Bangladesh. Specifically, it illustrates how private tutoring has emerged and expanded in the country's education system and examines how governments have responded on this issue.Design/methodology/approachThe authors adopted a case study methodology for this study. Data were gathered from different secondary sources such as books, official documents, scholarly articles, and newspaper reports. The data analysis process consists of three-phases of activities: data reduction, data display, and conclusion drawing/verification.FindingsPrivate tutoring historically existed in Bangladesh. It is rapidly expanded in the country's education system – from primary to higher secondary level. Currently, it has reached an industrialization stage, where commercial coaching has become a major type of tutoring. The expansion of private tutoring is the inevitable result of the continued privatization and marketization of education. To bring the private tutoring under a framework, the government has taken some regulatory measures that can be characterized as “laissez-faire.” The existing measures are largely ineffective, as the policy makers followed an “top-down” approach when framing the policies.Originality/valueThis study, to the best of the authors' knowledge, is the first to target the historical aspects of private tutoring in Bangladesh. It has potential to fill out the literature gap on private tutoring by analyzing its policy aspect.