bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impairment of SARS-CoV-2 spike-glycoprotein maturation and fusion-activity by nitazoxanide: an effect independent of spike variants emergence
Authors: Riccio Anna , Santopolo Silvia , Rossi Antonio , Piacentini Sara , Rossignol Jean-Francois , Santoro M. Gabriella 
Published: April 2021

ABSTRACTSARS-CoV-2, the causative agent of COVID-19, has caused an unprecedented global health crisis. The SARS-CoV-2 spike, a surface-anchored trimeric class-I fusion-glycoprotein essential for viral entry, represents a key target for developing vaccines and therapeutics capable of blocking virus invasion. The emergence of SARS-CoV-2 spike-variants that facilitate virus spread and may affect vaccine efficacy highlights the need to identify novel antiviral strategies for COVID-19 therapy. Here we demonstrate that nitazoxanide, an antiprotozoal agent with recognized broad-spectrum antiviral activity, interferes with SARS-CoV-2 spike biogenesis, hampering its maturation at an endoglycosidase H-sensitive stage. Engineering multiple SARS-CoV-2 variant-pseudoviruses and utilizing quantitative cell-cell fusion assays, we show that nitazoxanide-induced spike modifications hinder progeny virion infectivity as well as spike-driven pulmonary cell-cell fusion, a critical feature of COVID-19 pathology. Nitazoxanide, being equally effective against the ancestral SARS-CoV-2 Wuhan-spike and different emerging variants, including the Delta variant of concern, may represent a useful tool in the fight against COVID-19 infections.
Mutation rate dynamics reflect ecological change in an emerging zoonotic pathogen
Authors: Murray Gemma G. R. , Balmer Andrew J. , Herbert Josephine , Hadijirin Nazreen F. , Kemp Caroline L. , Matuszewska Marta , Bruchmann Sebastian , Mukarram Hossain A. S. Md. , Gottschalk Marcelo , Tucker A. W. (Dan) , Miller Eric , Weinert Lucy A. 
Published: April 2021

AbstractWhile mutation is often deleterious, it can also be adaptive. Mutation rates vary both within and between bacterial species, and understanding what drives this variation is essential for understanding the evolutionary dynamics of bacterial populations. In this study we investigate two factors that are predicted to influence the trade-off between the costs and benefits of mutation: ecology and genome size. To investigate the relationship between these factors and mutation rate we conducted mutation accumulation experiments on eight strains of the emerging zoonotic pathogenStreptococcus suis. Natural variation within this species allows us to compare tonsil carriage and invasive disease isolates, from both more and less pathogenic populations, with a wide range of genome sizes. We find that invasive disease isolates have repeatedly evolved mutation rates that are higher than those of closely related carriage isolates, regardless of variation in genome size. Independent of this variation in overall rate, we also observe a stronger bias towards G/C to A/T mutations in isolates from more pathogenic populations, whose genomes tend to be smaller and more AT-rich. Our results suggest that ecology is a stronger correlate of mutation rate than genome size over these timescales, and that transitions to invasive disease are consistently accompanied by rapid increases in mutation rate. These results shed light on the impact ecology can have on the adaptive potential of bacterial pathogens.
Activation of innate immune signalling during development predisposes to inflammatory intestine and shortened lifespan
Authors: Yamashita Kyoko , Oi Ayano , Kosakamoto Hina , Yamauchi Toshitaka , Kadoguchi Hibiki , Kuraishi Takayuki , Miura Masayuki , Obata Fumiaki 
Published: April 2021

AbstractEarly-life inflammatory response is associated with risks of age-related pathologies. How transient immune signalling activity during animal development influences life-long fitness is not well understood. UsingDrosophilaas a model, we find that activation of innate immune pathway IMD signalling in the developing larvae increases adult starvation resistance, decreases food intake, and shortens organismal lifespan. Interestingly, lifespan is shortened by the IMD activation in the larval gut and fat body, while starvation resistance and food intake are altered by that in neurons. The adult flies developed with IMD activation show sustained IMD activity in the gut, despite complete tissue renewal during metamorphosis. The inflammatory adult gut is associated with a greater amount ofGluconobactersp., characteristic gut microbiota increased in response to immune activation. Removing gut microbiota by antibiotics attenuates the increase of IMD activity and rescues the shortened lifespan. This study demonstrates a tissue-specific programming effect of early-life immune activation on the adult physiology and organismal lifespan.
How basic components of information-updating interact to encourage variation in the results of empirical studies of within and transgenerational plasticity
Authors: Stamps Judy A , Bell Alison M 
Published: April 2021

AbstractExperiences of parents and/or offspring are often assumed to affect the development of trait values in offspring because they provide information about the external environment, but it is currently unclear how information from different sources and times might combine to affect the information-states that provide the foundation for the patterns observed in empirical studies of developmental plasticity in response to environmental cues. We analyze Bayesian models designed to mimic fully-factorial experimental studies of within and transgenerational plasticity (TWP), in which parents, offspring, neither or both are exposed to cues from predators, to determine how different durations of cue exposure for parents and offspring, the devaluation of information from parents or the degradation of information from parents would affect offspring estimates of environmental states related to risk of predation at the end of such experiments. We show that the effects of different cue durations, the devaluation of information from parents, and the degradation of information from parents on offspring estimates are all expected to vary as a function of interactions with two other key parameters of information-based models of TWP: parental priors and the relative cue reliability in the different treatments. Our results suggest empiricists should expect to observe considerable variation across experimental studies of TWP based on simple principles of information-updating, without needing to invoke additional assumptions about costs, tradeoffs, development constraints, the fitness consequences of different trait values, or other factors.
The world’s hotspot of linguistic and biocultural diversity under threat
Authors: Kik Alfred , Adamec Martin , Aikhenvald Alexandra Y. , Bajzekova Jarmila , Baro Nigel , Bowern Claire , Colwell Robert K. , Drozd Pavel , Duda Pavel , Ibalim Sentiko , Jorge Leonardo R. , Mogina Jane , Ruli Ben , Sam Katerina , Sarvasy Hannah , Saulei Simon , Weiblen George D. , Zrzavy Jan , Novotny Vojtech 
Published: April 2021

AbstractPapua New Guinea is home to >10% of the world’s languages and rich and varied biocultural knowledge, but the future of this diversity remains unclear. We measured language skills of 6,190 students speaking 392 languages (5.5% of the global total) and modelled their future trends, using individual-level variables characterizing family language use, socio-economic conditions, student’s skills, and language traits. This approach showed that only 58% of the students, compared to 91% of their parents, were fluent in indigenous languages, while the trends in key drivers of language skills (language use at home, proportion of mixed-language families, urbanization, students’ traditional skills) predicted accelerating decline of fluency, to an estimated 26% in the next generation of students. Ethnobiological knowledge declined in close parallel with language skills. Varied medicinal plant uses known to the students speaking indigenous languages are replaced by a few, mostly non-native species for the students speaking English or Tok Pisin, the national lingua franca. Most (88%) students want to teach indigenous language to their children. While crucial for keeping languages alive, this intention faces powerful external pressures as key factors (education, cash economy, road networks, urbanization) associated with language attrition are valued in contemporary society.Significance StatementAround the world, more than 7,000 languages are spoken, most of them by small populations of speakers in the tropics. Globalization puts small languages at a disadvantage, but our understanding of the drivers and rate of language loss remains incomplete. When we tested key factors causing language attrition among Papua New Guinean students speaking 392 different indigenous languages, we found an unexpectedly rapid decline in their language skills compared to their parents and predicted further acceleration of language loss in the next generation. Language attrition was accompanied by decline in the traditional knowledge of nature among the students, pointing to an uncertain future for languages and biocultural knowledge in the most linguistically diverse place on Earth.
YTHDC2 Is Essential for Pachytene Progression and Prevents Aberrant Microtubule-Driven Telomere Clustering in Male Meiosis
Authors: Liu Rong , Kasowitz Seth D. , Homolka David , Leu N. Adrian , Shaked Jordan T. , Ruthel Gordon , Jain Devanshi , Keeney Scott , Luo Mengcheng , Pillai Ramesh S. , Wang P. Jeremy 
Published: April 2021

SUMMARYMechanisms driving the prolonged meiotic prophase I are poorly understood. The RNA helicase YTHDC2 is critical for mitosis to meiosis transition, as YTHDC2-deficient mouse germ cells initiate meiosis but arrest with mixed characteristics of mitotic and meiotic cell types. However, YTHDC2 is also highly expressed in normal pachytene cells. Here we identify an essential role for YTHDC2 in meiotic progression. Specifically, we find that YTHDC2 deficiency causes microtubule-dependent telomere clustering and apoptosis at the pachytene stage of prophase I, and thus a failure to advance to the diplotene stage. Depletion of YTHDC2 results in a massively dysregulated transcriptome in pachytene cells, with a tendency toward upregulation of genes normally expressed in mitotic germ cells and downregulation of meiotic transcripts. Dysregulation does not correlate with the m6A status of RNAs and YTHDC2-bound mRNAs are enriched in genes upregulated in mutant germ cells, revealing that YTHDC2 primarily targets its substrate mRNAs for degradation. Finally, altered transcripts in YTHDC2-deficient pachytene cells encode microtubule network proteins and inhibition of microtubule polymerization disperses clustered telomeres. Together, our results demonstrate that YTHDC2 regulates the prolonged pachytene stage of prophase I by perpetuating a meiotic transcriptome and preventing changes in the microtubule network that could lead to aberrant telomere clustering.
Modelling the impact of magnesium ions concentration on the folding of the SAM-II riboswitch
Authors: Alaidi Osama 
Published: April 2021

ABSTRACTRiboswitches are regulatory elements present in bacterial messenger RNA acting as sensors of small molecules and consequently playing a vital role in bacterial gene regulation. The SAM-II riboswitch is a class of riboswitches, that recognizes S-adenosyl methionine. It has been previously illustrated that the presence of Mg2+ions stabilizes the pre-existing minor state of the riboswitch, which is structurally characterised by having a nucleated pseudoknot, leading to the increase of its probability. In this study, an analytical equilibrium model is developed to describe the impact of Mg2+ions concentration on the folding of the SAM-II riboswitch, linking RNA folding and tertiary interactions energetics to ligand binding, and, hence enabling quantitative predictions. The method was used to study the role of the P1 helix sequence in determining the fraction of binding competent conformers of the SAM-II riboswitch, by simulating the Mg2+titration curves of various mutants.Graphical abstract
Elevated anti-SARS-CoV-2 antibodies and IL-6, IL-8, MIP-1β, early predictors of severe COVID-19
Authors: Codina Helena , Vieitez Irene , Gutierrez-Valencia Alicia , Skouridou Vasso , Martínez Cristina , Patiño Lucía , Botero-Gallego Mariluz , Trujillo-Rodríguez María , Serna-Gallego Ana , Muñoz-Muela Esperanza , Bobillo María M. , Pérez Alexandre , Cabrera-Alvar Jorge Julio , Crespo Manuel , O’Sullivan Ciara K. , Ruiz-Mateos Ezequiel , Poveda Eva 
Published: April 2021

ABSTRACTBackgroundViral and host immune kinetics during acute COVID-19 and after remission of acute symptoms need better characterization.MethodsSARS-CoV-2 RNA, anti-SARS-CoV-2 IgA, IgM, and IgG antibodies, and pro-inflammatory cytokines were measured in sequential samples among hospitalized COVID-19 patients during acute infection and 6 months following diagnosis.Results24 laboratory-confirmed COVID-19 patients with mild/moderate and severe COVID-19 were included. Most were males 83%, median age of 61 years. 21% were admitted to the ICU and 8 of them (33.3%) met criteria for severe COVID-19 disease. A delay in SARS-CoV-2 levels decline during the first 6 days of follow-up and viral load persistence until month 3 were related with severe COVID-19, but not viral load levels at the diagnosis. Higher levels of anti-SARS-CoV-2 IgA, IgM, IgG and the cytokines IL-6, IL-8 and MIP-1β at the diagnosis time were related with severe COVID-19 outcome. Higher levels of MIP-1β, IL-1β, MIP-1αand IFN-γwere observed at month 1/3 during mild/moderate disease compared to severe COVID-19. IgG persisted at low levels after 6 months of diagnosis.ConclusionsHigher concentrations of IgA, IgM, and IgG, and IL-6, IL-8 and MIP-1β are identified as early predictors of COVID-19 severity, but not SARS-CoV-2 RNA levels at diagnosis.
Mutations affecting the N-terminal domains of SHANK3 point to different pathomechanisms in neurodevelopmental disorders
Authors: Woike Daniel , Wang Emily , Tibbe Debora , Nia Fatemeh Hassani , Kibæk Maria , Larsen Martin J. , Fagerberg Christina R. , Barsukov Igor , Kreienkamp Hans-Jürgen 
Published: April 2021

AbstractShank proteins are major scaffolds of the postsynaptic density of excitatory synapses. Mutations inSHANKgenes are associated with autism and intellectual disability. The relevance of missense mutations for these pathologies is unclear. Several missense mutations inSHANK3affect the N-terminal region, consisting of the Shank/ProSAP N-terminal (SPN) domain and a set of Ankyrin (Ank) repeats. Here we identify a novelSHANK3missense mutation (p.L270M) in the Ankyrin repeats in patients with an ADHD-like phenotype. We functionally analysed this and a series of other mutations, using biochemical and biophysical techniques. We observe two major effects: (i) a loss of binding to δ-catenin (e.g. in the p.L270M variant), and (ii) interference with the intramolecular interaction between N-terminal SPN domain and the Ank repeats. This also interferes with binding to the α-subunit of the calcium-/calmodulin dependent kinase II (αCaMKII), and appears to be associated with a more severe neurodevelopmental pathology.
Closing Time
Authors: Hilario Jan , Meusel Maik , Pohl Walt , Schmedders Karl 
Published: April 2021

Jennifer McDougall is considering investing in mutual funds for the first time, and has narrowed her options down to three: one that is domiciled in Germany, and two that are domiciled in Luxembourg. As a cautious and risk-averse investor, Jennifer has done extensive research on the three funds, and has come across a curious fact: the beta of the German fund is surprisingly low. After speaking to her financial planner, she learns there is no legal requirement in Germany for mutual funds to compute net asset values at a particular time of the day. If the German fund is closing its books in the middle of the day and its net asset values reflect its midday holdings, rather than end-of-day holdings, this could explain the low beta. Thus, the German fund might appear less risky, without actually being so. Jennifer needed to get a clearer picture of what was going on before making her decision.
Using the data provided with the case, students will determine the closing time of the three funds and how that affects the beta of each. Then they must make a recommendation about which fund would be the best investment for Jennifer.
Starbucks: Driving Growth Through New Dining Occasions
Authors: Sawhney Mohanbir 
Published: April 2021

In 2008, Starbucks was in crisis as a result of undisciplined growth and loss of focus, and its stock declined almost 70%. In August of that year, Howard Schultz, the founder of Starbucks, came out of retirement to take over as the CEO. The company regained its footing by refocusing on its core and driving strong organic growth. By 2014, the stock price had reached $40, an all-time high. To prevent history from repeating itself, Schultz wanted to ensure that Starbucks' growth strategies not only addressed market opportunities, but also were aligned with the company's brand image, assets, and capabilities.
Starbucks announced a five-year growth plan in December 2014 with ambitious goals that included nearly doubling its revenues from $16 billion to $30 billion, doubling operating income, and expanding its footprint to more than 30,000 stores globally by 2019. The growth plan consisted of seven specific growth strategies, one of which was the New Occasions strategy. The objective of New Occasions was to drive growth by diversifying Starbucks' revenues beyond breakfast to the lunch, afternoon, and evening dayparts. Starbucks created specific offerings for each daypart, called the Lunch, Sunset, and Evenings programs. The case focuses on evaluating these three occasions-based growth opportunities and identifying the best path forward.
The Trouble with Lenders: Subtleties in the Debt Financing of Commercial Real Estate
Authors: Furfine Craig 
Published: April 2021

With interest rates near all-time lows in late 2015, Stanley Cirano knew it was an opportune time to consider the financing on his portfolio of commercial real estate. Cirano Properties was the general partner on three separate private equity investments of retail shopping centers in suburban Chicago. The first, Brookline Road Shopping Center, had been acquired in 2006 and had been managed through the financial crisis and real estate downturn. The property was performing well and Cirano wondered whether it made sense to refinance or sell. The second property, Columbus Festival Plaza, had been acquired in a 2010 bankruptcy auction. Although the property had needed a good amount of capital improvements, Cirano was proud of the growth in net operating income he had been able to generate. The final property, Deerwood Acres, had been developed by Cirano himself after acquiring the property in 2013 from the previous owner, who had been operating a go-cart track and drive-in theater on the land. Cirano expected great things from the property, though his lease-up had been slower than anticipated.
Although the three properties had different levels of performance and presented different management issues, they all shared the fact that they were all significantly financed, in part, with debt. As the properties were acquired at different times, Cirano had simply selected what seemed like reasonable financing at the time. With his concern that interest rates would soon be rising, Cirano thought it made sense to take a holistic view of his portfolio, consider what debt options were available to him, and make a sound strategic decision on the financing of all his assets at the same time.
Measuring and Managing Risk in Commodities: Corn and the Golden Kernel
Authors: Walker Russell 
Published: April 2021

Risk managers have more tools than ever to help protect their companies from risk. Complex financial instruments, intricate mathematical models, and access to massive amounts of data can help the risk manager structure a multifaceted strategy to decrease volatility and protect the company from a catastrophic event. However, these tools have their own risks that can complicate a risk manager's job.
Analyzing corn price volatility helps students understand four best practices for risk managers, regardless of the specific risks they face or the strategies they employ: quantify the company's exposure; understand the nature of the risk; understand how the hedge works in practice; and separate hedging and speculation.
The Hunger Games: Catching Fire: Using Digital and Social Media for Brand Storytelling
Authors: Sawhney Mohanbir , Goodman Pallavi 
Published: April 2021

After the successful release of the first Hunger Games film in 2012, the film's distributor, Lionsgate, was preparing to release the next movie in the series, Hunger Games: Catching Fire. Fan expectations had grown after the success of the first film, and Lionsgate faced the challenge of keeping moviegoers interested and engaged in another Hunger Games movie. In an era marked by the rising popularity of digital and social media, Lionsgate knew that attracting fans to a sequel meant pushing the boundaries of traditional marketing tactics.
Digital brand storytelling is about using digital media in a holistic way to tell a brand story and build excitement for an audience. Brand storytelling seeks to make a connection with the audience by giving them an emotional experience that resonates with them. While Lionsgate was aware that traditional marketing would need to be blended with a digital campaign to bring in moviegoers, it also needed to strike a careful balance between the two and choose the appropriate platforms to tell a cohesive story. Should Lionsgate launch a brand storytelling campaign to appeal to fans? Lionsgate's comparatively small marketing team gathered to brainstorm about how to execute such a campaign and position the film for another big success.
Saks Fifth Avenue and Transgender Rights
Authors: Feddersen Timothy 
Published: April 2021

In September 2014 Leyth Jamal, a transgender woman, filed suit against her employer, luxury retailer Saks Fifth Avenue. Jamal alleged that she experienced harassment from managers and other employees because of her gender identity while employed by Saks, including verbal abuse and threats of violence. At the time she filed suit, no federal, state, or local laws protected transgender employees from discrimination. However, some federal district courts had recently begun to allow such suits on the premise that discrimination based on gender identity was a form of sex discrimination. Other suits and amicus briefs brought by the Equal Employment Opportunity Commission (EEOC) furthered this trend. The EEOC is the federal agency charged with investigating and supporting claims of discrimination under Title VII of the Civil Rights Act of 1964, so district and appellate courts watched the EEOC's position on the application of Title VII. Socio-culturally, many Americans supported transgender rights, even as they voiced anxiety about transgender men in women's bathrooms.
This case has students assume the role of a trusted member of the executive team of Hudson's Bay Company, which owns Saks Fifth Avenue. One Friday afternoon in late December 2014, the Hudson's Bay CEO sends an email to his executive team notifying them that he has approved corporate counsel's motion to dismiss Jamal's case based on the argument that transgender people are not a protected class according to Title VII. The motion will be filed in federal court on Monday. The CEO shares that he personally believes it is preposterous for anyone to think that Saks Fifth Avenue is anything but a strong advocate for LGBT rights, but he invites executive team members to call him if they have any concerns. Members of the executive team have a responsibility to consider the broader strategic implications for the company, so students must decide if and how to respond to the CEO.