bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein-protein interactions in neurodegenerative diseases: a conspiracy theory
Authors: Thompson Travis B. , Chaggar Pavanjit , Kuhl Ellen , Goriely Alain ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: February 2020

AbstractNeurodegenerative diseases such as Alzheimer’s or Parkinson’s are associated with the prion-like propagation and aggregation of toxic proteins. A long standing hypothesis that amyloid-beta drives Alzheimer’s disease has proven the subject of contemporary controversy; leading to new research in both the role of tau protein and its interaction with amyloid-beta. Conversely, recent work in mathematical modeling has demonstrated the relevance of nonlinear reaction-diffusion type equations to capture essential features of the disease. Such approaches have been further simplified, to network-based models, and offer researchers a powerful set of computationally tractable tools with which to investigate neurodegenerative disease dynamics.Here, we propose a novel, coupled network-based model for a two-protein system that includes an enzymatic interaction term alongside a simple model of aggregate transneuronal damage. We apply this theoretical model to test the possible interactions between tau proteins and amyloid-beta and study the resulting coupled behavior between toxic protein clearance and proteopathic phenomenology. Our analysis reveals ways in which amyloid-beta and tau proteins may conspire with each other to enhance the nucleation and propagation of different diseases, thus shedding new light on the importance of protein clearance and protein interaction mechanisms in prion-like models of neurodegenerative disease.Author SummaryIn 1906 Dr. Alois Alzheimer delivered a lecture to the Society of Southwest German Psychiatrists. Dr. Alzheimer presented the case of Ms. Auguste Deter; her symptoms would help to define Alzheimer’s disease (AD). Over a century later, with an aging world population, AD is at the fore of global neurodegenerative disease research. Previously, toxic amyloid-beta protein (Aβ) was thought to be theprimarydriver of AD development. Recent research suggests that another protein, tau, plays a fundamental role. Toxic tau protein contributes to cognitive decline and appears to interact with toxic Aβ; research suggests that toxic Aβmay further increase the effects of toxic tau.Theoretical mathematical models are an important part of neurodegenerative disease research. Such models: enable extensible computational exploration; illuminate emergent behavior; and reduce research costs. We have developed a novel, theoretical mathematical model of two interacting species of proteins within the brain. We analyze the mathematical model and demonstrate a computational implementation in the context of Aβ-tau interaction in the brain. Our model clearly suggests that: the removal rate of toxic protein plays a critical role in AD; and the Aβ-tau ‘conspiracy theory’ is a nuanced, and exciting path forward for Alzheimer’s disease research.
Phosphorylation controls RNA binding and transcription by the influenza virus polymerase
Authors: Dawson Anthony R. , Wilson Gary M. , Freiberger Elyse C. , Mondal Arindam , Coon Joshua J. , Mehle Andrew 
Published: February 2020

AbstractThe influenza virus polymerase transcribes and replicates the viral genome. The proper timing and balance of polymerase activity is important for successful replication. We previously showed that phosphorylation regulates genome replication by controlling assembly of the replication machinery (Mondal, et al. 2017). However, it remained unclear whether phosphorylation directly regulated polymerase activity. Here we identified polymerase phosphosites that control its function. Mutating phosphosites in the catalytic subunit PB1 altered polymerase activity and virus replication. Biochemical analyses revealed phosphorylation events that disrupted global polymerase function by blocking the NTP entry channel or preventing RNA binding. We also identified a regulatory site that split polymerase function by specifically suppressing transcription. These experiments show that host kinases phospho-regulate viral RNA synthesis directly by modulating polymerase activity and indirectly by controlling assembly of replication machinery. Further, they suggest polymerase phosphorylation may bias replication versus transcription at discrete times or locations during the infectious cycle.
An essential membrane protein modulates the proteolysis of LpxC to control lipopolysaccharide synthesis inEscherichia coli
Authors: Fivenson Elayne M. , Bernhardt Thomas G. 
Published: February 2020

ABSTRACTGram-negative bacteria are surrounded by a complex cell envelope that includes two membranes. The outer membrane prevents many drugs from entering these cells and is thus a major determinant of their intrinsic antibiotic resistance. This barrier function is imparted by the asymmetric architecture of the membrane with lipopolysaccharide (LPS) in the outer leaflet and phospholipids in the inner leaflet. The LPS and phospholipid synthesis pathways share a common intermediate. Proper membrane biogenesis therefore requires that the flux through each pathway be balanced. InEscherichia coli, a major control point in establishing this balance is the committed step of LPS synthesis mediated by LpxC. Levels of this enzyme are controlled through its degradation by the inner membrane protease FtsH and its presumed adaptor protein LapB(YciM). How turnover of LpxC is controlled has remained unclear for many years. Here, we demonstrate that the essential protein of unknown function YejM(PbgA), which we have renamed ClxD (control ofLpxCdegradation), participates in this regulatory pathway. Suppressors of ClxD essentiality were identified inlpxCandlapB, and LpxC overproduction was shown to be sufficient to allow survival of ΔclxDmutants. Furthermore, the half-life of LpxC was shown to be reduced in cells lacking ClxD, and genetic and physical interactions between LapB and ClxD were detected. Taken together, our results are consistent with a model in which ClxD directly modulates LpxC turnover by FtsH-LapB to regulate LPS synthesis and maintain membrane homeostasis.SIGNIFICANCEThe outer membrane is a major determinant of the intrinsic antibiotic resistance of Gram-negative bacteria. It is composed of both lipopolysaccharide (LPS) and phospholipid, and the synthesis of these lipid species must be balanced for the membrane to maintain its barrier function in blocking drug entry. In this report, we identify an essential protein of unknown function as a key new factor in maintaining LPS/phospholipid balance in the model bacteriumEscherichia coli. Our results provide novel insight into how this organism and most likely other Gram-negative bacteria maintain membrane homeostasis and their intrinsic resistance to antibiotics.
ΦX174 Attenuation by Whole Genome Codon Deoptimization
Authors: Van Leuven James T. , Ederer Martina M. , Burleigh Katelyn , Scott LuAnn , Hughes Randall A. , Codrea Vlad , Ellington Andrew D. , Wichman Holly , Miller Craig 
Published: February 2020

AbstractNatural selection acting on synonymous mutations in protein-coding genes influences genome composition and evolution. In viruses, introducing synonymous mutations in genes encoding structural proteins can drastically reduce viral growth, providing a means to generate potent, live attenuated vaccine candidates. However, an improved understanding of what compositional features are under selection and how combinations of synonymous mutations affect viral growth is needed to predictably attenuate viruses and make them resistant to reversion. We systematically recoded all non-overlapping genes of the bacteriophage ΦX174 with codons rarely used in itsE. colihost. The fitness of recombinant viruses decreases as additional deoptimizing mutations are made to the genome, although not always linearly, and not consistently across genes. Combining deoptimizing mutations may reduce viral fitness more or less than expected from the effect size of the constituent mutations and we point out difficulties in untangling correlated compositional features. We test our model by optimizing the same genes and find that the relationship between codon usage and fitness does not hold for optimization, suggesting that wild-type ΦX174 is at a fitness optimum. This work highlights the need to better understand how selection acts on patterns of synonymous codon usage across the genome and provides a convenient system to investigate the genetic determinants of virulence.
Varicella-Zoster Virus ORF9 Is an Antagonist of the DNA Sensor cGAS
Authors: Hertzog Jonny , Zhou Wen , Rigby Rachel E. , Fowler Gerissa , Cursi Chiara , Chauveau Lise , Davenne Tamara , Kranzusch Philip J. , Rehwinkel Jan 
Published: February 2020

SUMMARYVaricella-Zoster virus (VZV) causes chickenpox and shingles. Although infection is associated with severe morbidity in some individuals, molecular mechanisms that determine innate immune responses remain poorly defined. We found that the cGAS/STING DNA sensing pathway was required for type I interferon (IFN) induction during VZV infection and that recognition of VZV by cGAS restricted its replication. Viral gene overexpression screening identified the essential VZV tegument protein ORF9 as a cGAS antagonist. Ectopically and virally expressed ORF9 bound to endogenous cGAS. Confocal microscopy revealed co-localisation of cGAS and ORF9, which reduced the type I IFN response to transfected DNA. ORF9 and cGAS also interacted directly in a cell-free system and phase-separated together with DNA. Furthermore, ORF9 inhibited cGAMP production by cGAS. Taken together, we uncovered the importance of the cGAS/STING DNA sensing pathway for VZV recognition and identified a VZV immune antagonist that directly interferes with DNA sensing via cGAS.
Corporation blameworthiness and federal criminal fines
Authors: Homer Emily M. , Higgins George E. 
Published: February 2020

Purpose
The purpose of this paper is to assess if federal judges have sentenced criminal corporations to fines that are consistent with the seriousness of the offense and the blameworthiness of the organization, which would be in line with the directives from the US Sentencing Guidelines. This paper will also use the focal concerns framework to measure organizational blameworthiness.

Design/methodology/approach
This paper uses secondary data from federal sentencing documents, collected by the US Sentencing Commission, for cases that were adjudicated between October 1, 2010 and September 30, 2017.

Findings
Results showed that the focal concerns framework can be used to define potential constructs for blameworthiness and that an organization’s culpability score was a significant predictor in whether the company received a higher fine.

Research limitations/implications
The data are unable to examine two of the three measures of focal concerns. Cross-sectional data limits the ability to draw conclusions regarding cause and effect between blameworthiness and monetary fines.

Practical implications
Results imply that judges are sentencing corporations that have higher culpability scores to more severe fines, in accordance with both the federal Sentencing Guidelines and focal concerns framework.

Originality/value
This study is one of the first to apply the focal concerns framework, usually used to examine the sentencing of individuals, to the sentencing of corporations. It is also one of the first to attempt to empirically define blameworthiness.
Technology adoption news and corporate reputation: sentiment analysis about the introduction of Bitcoin
Authors: Caviggioli Federico , Lamberti Lucio , Landoni Paolo , Meola Paolo 
Published: February 2020

PurposeEvidence from previous literature indicates that adopting a new innovative technology has a positive impact on a company’s business performance. Much less work has been carried out into examining whether a technology adoption has impact on corporate reputation. This paper aims to examine the latter topic in a context where social media is the channel used to share news about the introduction of a new technology. The empirical setting of the study consists of five retail companies located in the USA that decided to include Bitcoin as a payment platform.Design/methodology/approachTwitter data were used to measure how sharing news about the adoption of new technology could affect the reputation of the companies selected, keeping a clear distinction between the volume of data relating to social media responses and the sentiment expressed in the tweets. A panel vector autoregression model was used to incorporate series of data relating to news items, volume and sentiment.FindingsThe results show that the news about the adoption of a new technology has a positive impact on both the volume of tech-related tweets and the sentiment expressed in the tweets themselves, although the patterns of these two effects are different. The resulting impact decreases after a few days, both in volume and in sentiment.Research limitations/implicationsThe analysis has limitations that future research could address by extending and diversifying the examined companies and the social media used as data sources. The research suggests that managers in medium-sized companies can leverage on the introduction of new technologies that have a direct impact on their customers and gain reputational benefits in terms of immediate visibility.Originality/valueThe research introduces an additional dimension of analysis to the current stream of corporate reputation. Although the literature has already covered the dynamics of response to events on Twitter, by focusing on the adoption of the new Bitcoin technology, the paper provides novel insights.
Viewpoint: getting your qualitative service research published
Authors: Holmlund Maria , Witell Lars , Gustafsson Anders 
Published: February 2020

Purpose
The purpose of this paper is to provide authors with guidelines for carrying out excellent qualitative service research. It describes the features that editors and reviewers use to evaluate qualitative research and pinpoints what authors can do to improve their manuscripts for publication.

Design/methodology/approach
The paper identifies five features of excellent qualitative service research – relevance, rigor, integrity, narration and impact – and describes them with a focus on what they mean and what authors can do to meet these standards.

Findings
The paper suggests that manuscripts are often rejected because they fail to meet key standards of excellent qualitative research. It calls for more discussion on research methodology and research ethics, especially when service research strives to make a difference such as investigating critical service contexts or dealing with vulnerable participants.

Originality/value
This paper contributes to a better use and application of qualitative research methodology. It focuses on specific actions that researchers can take to improve the quality of their service research manuscripts.
Evidence based policing: a view on its development within the police service
Authors: Pepper Ian , Rogers Colin , Martin Helen 
Published: February 2020

PurposeAs the education of new police constables moves to degree level, this paper explores the introduction of Evidence-Based Policing (EBP) as a pillar of the evolution of the police service as a profession.Design/methodology/approachCombining a review of key literature and explorations of practice, the current situation, challenges, and benefits of the adoption of EBP as philosophy are explored.FindingsThe benefits to the police service and individuals of wholeheartedly adopting EBP are huge; however, such adoption does not come without challenges.Originality/valueThis paper provides a contemporary snapshot in relation to the process of embedding EBP across the new educational routes to joining the police service. The opportunities provided by adopting EBP as philosophy across the service will assist in supporting and strengthening the sustainability of policing locally, nationally, and internationally.
Effective elastic moduli of metal honeycombs manufactured using selective laser melting
Authors: Hussein Rafid , Anandan Sudharshan , Spratt Myranda , Newkirk Joseph W. , Chandrashekhara K. , Heath Misak , Walker Michael 
Published: February 2020

Purpose
Honeycomb cellular structures exhibit unique mechanical properties such as high specific strength, high specific stiffness, high energy absorption and good thermal and acoustic performance. This paper aims to use numerical modeling to investigate the effective elastic moduli, in-plane and out-of-plane, for thick-walled honeycombs manufactured using selective laser melting (SLM).

Design/methodology/approach
Theoretical predictions were performed using homogenization on a sample scale domain equivalent to the as-manufactured dimensions. A Renishaw AM 250 machine was used to manufacture hexagonal honeycomb samples with wall thicknesses of 0.2 to 0.5 mm and a cell size of 3.97 mm using 304 L steel powder. The SLM-manufactured honeycombs and cylindrical test coupons were tested using flatwise and edgewise compression. Three-dimensional finite element and strain energy homogenization were conducted to determine the effective elastic properties, which were validated by the current experimental outcomes and compared to analytical models from the literature.

Findings
Good agreement was found between the results of the effective Young’s moduli ratios numerical modeling and experimental observations. In-plane effective elastic moduli were found to be more sensitive to geometrical irregularity compared to out-of-plane effective moduli, which was confirmed by the analytical models. Also, it was concluded that thick-walled SLM manufactured honeycombs have bending-dominated in-plane compressive behavior and a stretch-dominated out-of-plane compressive behavior, which matched well with the simulation and numerical models predictions.

Originality/value
This work uses three-dimensional finite element and strain energy homogenization to evaluate the effective moduli of SLM manufactured honeycombs.
Rita McGrath: anticipating and exploiting strategic inflection points
Authors: Leavy Brian 
Published: February 2020

Purpose
An interview with Rita McGrath a pioneer of “discovery-driven planning,” now widely recognized as one of the most effective approaches for strategy development in the face of uncertainty.

Design/methodology/approach
Her research and experience interacting with executive teams positions her to offer corporate leaders practical perspectives and advice on how to approach strategically the great opportunities and dangers that lie ahead in this VUCA environment.

Findings
Major inflection points that create real change unfold gradually, then suddenly. Because they do take a while to unfold, an astute strategist who was paying attention to the signs could take advantage of the inflection. The future doesn’t happen all at once. It begins to unfold unevenly, and if you can “interview” where it is starting to take place now, you can begin to develop an early point of view about it.

Practical implications
There’s no substitute for watching how customers interact with your product or service and listening to their conversations about their experience.

Originality/value
McGrath’s thesis is when an inflection point does indeed reach a tipping point, it can feel as though it came out of nowhere. Her advice: if you are making a series of small options-style investments that are at the “edges” of your mainstream activities, you are likely to pick up on weak signals that allow you to, in an optimistic scenario, surf along an inflection point so that when the opportunity presents itself, you can move with speed to capture an advantage.
Evaluating the causal impact of individual alcohol licensing decisions on local health and crime using natural experiments with synthetic controls
Authors: de Vocht Frank , McQuire Cheryl , Brennan Alan , Egan Matt , Angus Colin , Kaner Eileen , Beard Emma , Brown Jamie , De Angelis Daniela , Carter Nick , Murray Barbara , Dukes Rachel , Greenwood Elizabeth , Holden Susan , Jago Russell , Hickman Matthew 
Published: February 2020

AbstractBackground and AimsGiven the costs of alcohol to society, it is important to evaluate whether local alcohol licensing decisions can mitigate the effects of alcohol misuse. Robust natural experiment evaluations of the impact of individual licensing decisions could potentially inform and improve local decision‐making. We aimed to assess whether alcohol licensing decisions could be evaluated at small spatial scale by using a causal inference framework.DesignThree natural experiments.Setting and participantsThree English local areas of 1000–15 000 people each.Intervention and comparatorThe case study interventions were (i) the closure of a nightclub following reviews; (ii) closure of a restaurant/nightclub following reviews and (iii) implementation of new local licensing guidance (LLG). Trends in outcomes were compared with synthetic counterfactuals created using Bayesian structural time–series.MeasurementsTime–series data were obtained on emergency department admissions, ambulance call‐outs and alcohol‐related crime at the Lower or Middle Super Output geographical aggregation level.FindingsClosure of the nightclub led to temporary 4‐month reductions in antisocial behaviour (−18%; 95% credible interval − 37%, −4%), with no change in other outcomes. Closure of the restaurant/nightclub did not lead to measurable changes in outcomes. The new licensing guidance led to small reductions in drunk and disorderly behaviour (nine of a predicted 21 events averted), and the unplanned end of the LLG coincided with an increase in domestic violence of two incidents per month.ConclusionsThe impact of local alcohol policy, even at the level of individual premises, can be evaluated using a causal inference framework. Local government actions such as closure or restriction of alcohol venues and alcohol licensing may have a positive impact on health and crime in the immediate surrounding area.
The natural history of congenital hypothyroidism with delayed TSH elevation in neonatal intensive care newborns
Authors: Zung Amnon , Radi Alin , Almashanu Shlomo 
Published: February 2020

AbstractObjectiveTo assess the clinical and neurological outcomes in newborns with primary congenital hypothyroidism presented with delayed TSH elevation (dTSH), and to define parameters that may predict the evolution of transient vs. permanent hypothyroidism in these newborns.Design and patientsAn observational study was performed of a cohort of 113 children with a history of dTSH.MeasurementsBirth parameters, thyroid screening results, thyroid gland imaging, levothyroxine dose and neurological outcome were compared between newborns with spontaneous recovery and children with a final diagnosis of either transient or permanent hypothyroidism.ResultsOf the children with a history of dTSH, 93% demonstrated recovery, either spontaneously or following levothyroxine treatment (transient hypothyroidism). Newborns with spontaneous recovery demonstrated milder thyroid dysfunction at the newborn screening compared to those who started levothyroxine treatment. Levothyroxine dose was lower in children with transient vs. permanent hypothyroidism only during the first 6 months of life; otherwise, these groups were similar in birth parameters, thyroid screening results and gland images. Seventeen out of 61 children (28%) that underwent neurological assessment demonstrated a developmental delay. Duration of treatment was highly variable in children with transient hypothyroidism.ConclusionsThyroid dysfunction is transient in most cases of dTSH. No reliable parameters can predict a priori transient vs. permanent hypothyroidism.