bluuebunny/crossref_metadata_2025_split huggingface dataset:
Porcine model elucidates function of p53 isoform in carcinogenesis
Authors: Niu Guanglin , Hellmuth Isabel , Flisikowska Tatiana , Pausch Hubert , Rieblinger Beate , Carrapeiro Alexander , Schade Benjamin , Böhm Brigitte , Kappe Eva , Fischer Konrad , Klinger Bernhard , Steiger Katja , Burgkart Reiner , Bourdon Jean-Christophe , Saur Dieter , Kind Alexander , Schnieke Angelika , Flisikowski Krzysztof 
Published: September 2020

AbstractBackgroundThe pig has long been an important animal species for biomedical research. Recent years has also seen an increasing number of genetically engineered pig models of human diseases including cancer. We previously generated pigs with a modifiedTP53allele which carries a Cre-removable transcriptional stop signal in intron 1, and an oncogenic mutationTP53R167H(orthologous to humanTP53R175Hand mouseTrp53R172H) in exon 5. Pigs with the unrecombined mutant allele (flTP53R167H) develop osteosarcoma (OS) in aged heterozygous and young homozygous animals. In addition, some homozygous animals also developed nephroblastomas and lymphomas. This observation suggested thatTP53gene dysfunction is itself the key initiator of tumorigenesis, but raises the question which aspects of theTP53regulation leads to the development of such a narrow tumour spectrum, mainly OS.MethodsWe performed a series of molecular and cellular analyses to study the regulation ofTP53and its family members in both healthy tissue and tumours (n= 48) from flTP53R167Hpigs. Human OS cell lines were used to prove relevance to human patients.ResultsMolecular analyses of p53 revealed the presence of two internalTP53promoters (Pint and P2) equivalent to those found in human. Consequently, both pigs and human expressTP53isoforms. Data presented here strongly suggest that P2-driven expression of the mutant R167H-Δ152p53 isoform (equivalent to the human R175H-Δ160p53 isoform) and its circular counterpartcircTP53determine the tumour spectrum and play a critical role in the malignant transformation of bones, kidney or spleen in flTP53R167Hpigs. The detection of Δ152p53 isoform mRNA in serum is indicative of tumorigenesis. Furthermore, we showed a tissue-specific p53-dependent deregulation of the p63 and p73 isoforms in these tumours.ConclusionsThis study highlights important species-specific differences in the transcriptional regulation ofTP53. For the first time acircTP53RNA was identified. Results indicate that the Δ152p53 isoform, its circularcircTP53and p53 family members, TAp63δ and TAp73δ, likely play a role in the malignant transformation of bone and other tumours. Considering the similarities ofTP53regulation between pig and human, these observations provide useful pointers for further investigation into isoform function including the novelcircTP53in both the pig model and human patients.
A dopamine gradient controls access to distributed working memory in monkey cortex
Authors: Froudist-Walsh Sean , Bliss Daniel P. , Ding Xingyu , Jankovic-Rapan Lucija , Niu Meiqi , Knoblauch Kenneth , Zilles Karl , Kennedy Henry , Palomero-Gallagher Nicola , Wang Xiao-Jing 
Published: September 2020

SummaryDopamine is critical for working memory. However, its effects throughout the large-scale primate cortex are poorly understood. Here we report that dopamine receptor density per neuron, measured by receptor autoradiography in the macaque monkey cortex, displays a macroscopic gradient along the cortical hierarchy. We developed a connectome- and biophysically-based model for distributed working memory that incorporates multiple neuron types and a dopamine gradient. The model captures an inverted U-shaped dependence of working memory on dopamine. The spatial distribution of mnemonic persistent activity matches that observed in over 90 experimental studies. We show that dopamine filters out irrelevant stimuli by enhancing inhibition of pyramidal cell dendrites. The level of cortical dopamine can also determine whether memory encoding is through persistent activity or an internal synaptic state. Taken together, our work represents a cross-level understanding that links molecules, cell types, recurrent circuit dynamics and a core cognitive function distributed across the cortex.
Functional myeloid-derived suppressor cells expand in blood but not airways of COVID-19 patients and predict disease severity
Authors: Falck-Jones Sara , Vangeti Sindhu , Yu Meng , Falck-Jones Ryan , Cagigi Alberto , Badolati Isabella , Österberg Björn , Lautenbach Maximilian Julius , Åhlberg Eric , Lin Ang , Szurgot Inga , Lenart Klara , Hellgren Fredrika , Sälde Jörgen , Albert Jan , Johansson Niclas , Bell Max , Loré Karin , Färnert Anna , Smed-Sörensen Anna 
Published: September 2020

AbstractThe immunopathology of COVID-19 remains enigmatic, exhibiting immunodysregulation and T cell lymphopenia. Monocytic myeloid-derived suppressor cells (M-MDSC) are T cell suppressors that expand in inflammatory conditions, but their role in acute respiratory infections remains unclear. We studied blood and airways of COVID-19 patients across disease severity at multiple timepoints. M-MDSC frequencies were elevated in blood but not in nasopharyngeal or endotracheal aspirates of COVID-19 patients compared to controls. M-MDSCs isolated from COVID-19 patients suppressed T cell proliferation and IFNγ production partly via an arginase-1 (Arg-1) dependent mechanism. Furthermore, patients showed increased Arg-1 and IL-6 plasma levels. COVID-19 patients had fewer T cells, and displayed downregulated expression of the CD3ζ chain. Ordinal regression showed that early M-MDSC frequency predicted subsequent disease severity. In conclusion, M-MDSCs expand in blood of COVID-19 patients, suppress T cells and strongly associate with disease severity, suggesting a role for M-MDSCs in the dysregulated COVID-19 immune response.
Application of an ecology-based analytic approach to discriminate signal and noise in low-biomass microbiome studies: whole lung tissue is the preferred sampling method for amplicon-based characterization of murine lung microbiota
Authors: Baker Jennifer M. , Hinkle Kevin J. , McDonald Roderick A. , Falkowski Nicole R. , Huffnagle Gary B. , Dickson Robert P. 
Published: September 2020

AbstractBackgroundLow-biomass microbiome studies (such as those of the lungs, placenta, and skin) are vulnerable to contamination and sequencing stochasticity, which obscure legitimate microbial signal. Since low-biomass microbiome fields have had variable success in establishing the reality and clinical significance of identified microbiota, we sought to develop and apply an analytical approach to discriminate signal from noise in low-biomass microbiome studies. We used this approach to determine the optimal sampling strategy in murine lung microbiome studies, which will be essential for future mechanistic lung microbiome research.MethodsUsing a novel, ecology-based analytic approach, we compared bacterial DNA from the lungs of healthy adult mice collected via two common sampling approaches: homogenized whole lung tissue and bronchoalveolar lavage (BAL) fluid. We quantified bacterial DNA using droplet digital PCR, characterized bacterial communities using 16S rRNA gene sequencing, and systematically assessed the quantity and identity of bacterial DNA in both specimen types. We compared bacteria detected in lung specimens to each other and to potential source communities: negative (background) control specimens and paired oral samples.FindingsBy all measures, whole lung tissue in mice contained greater bacterial signal and less evidence of contamination than did BAL fluid. Relative to BAL fluid, whole lung tissue exhibited a greater quantity of bacterial DNA, distinct community composition, decreased sample-to-sample variation, and greater biological plausibility when compared to potential source communities. In contrast, bacteria detected in BAL fluid were minimally different from those of procedural, reagent, and sequencing controls.InterpretationAn ecology-based analytical approach discriminates signal from noise in low-biomass microbiome studies and identifies whole lung tissue as the preferred specimen type for murine lung microbiome studies. Sequencing, analysis, and reporting of potential source communities, including negative control specimens and contiguous biological sites, is crucial for biological interpretation of low-biomass microbiome studies, independent of specimen type.FundingNational Institutes of Health
BURST enables mathematically optimal short-read alignment for big data
Authors: Al-Ghalith Gabriel , Knights Dan 
Published: September 2020

AbstractOne of the fundamental tasks in analyzing next-generation sequencing data is genome database search, in which DNA sequences are compared to known reference genomes for identification or annotation. Although algorithms exist for optimal database search with perfect sensitivity and specificity, these have largely been abandoned for next-generation sequencing (NGS) data in favor of faster heuristic algorithms that sacrifice alignment quality. Virtually all DNA alignment tools that are commonly used in genomic and metagenomic database search use approximate methods that sometimes report the wrong match, and sometimes fail to find a valid match when present. Here we introduce BURST, a high-throughput DNA short-read aligner that uses several new synergistic optimizations to enable provably optimal alignment in NGS datasets. BURST finds all equally good matches in the database above a specified identity threshold and can either report all of them, pick the most likely among tied matches, or provide lowest-common-ancestor taxonomic annotation among tied matches. BURST can align, disambiguate, and assign taxonomy at a rate of 1,000,000 query sequences per minute against the RefSeq v82 representative prokaryotic genome database (5,500 microbial genomes, 19GB) at 98% identity on a 32-core computer, representing a speedup of up to 20,000-fold over current optimal gapped alignment techniques. This may have broader implications for clinical applications, strain tracking, and other situations where fast, exact, extremely sensitive alignment is desired.
Structural characterization of Nonstructural protein 1 from SARS-CoV-2
Authors: Semper Cameron , Watanabe Nobuhiko , Savchenko Alexei 
Published: September 2020

AbstractSevere acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2) is a single-stranded, enveloped RNA virus and the etiological agent of the current COVID-19 pandemic. Efficient replication of the virus relies on the activity of nonstructural protein 1 (Nsp1), a major virulence factor shown to facilitate suppression of host gene expression through promotion of host mRNA degradation and interaction with the 40S ribosomal subunit. Here, we report the crystal structure of the globular domain of SARS-CoV-2 Nsp1, encompassing residues 13 to 127, at a resolution of 1.65 Å. Our structure features a six-stranded, capped β-barrel motif similar to Nsp1from SARS-CoV and reveals how variations in amino acid sequence manifest as distinct structural features. Through comparative analysis of structural homologues, we identified a topological signature associated with this protein fold that facilitated modeling of Nsp1 from MERS-CoV. Combining our high-resolution crystal structure with existing data on the C-terminus of Nsp1 from SARS-CoV-2, we propose a model of the full-length protein. Our results provide unparalleled insight into the molecular structure of a major pathogenic determinant of SARS-CoV-2.
Dysregulation of adipose ILC2 underlies thermogenic failure in aging
Authors: Goldberg Emily L. , Shchukina Irina , Youm Yun-Hee , Camell Christina D. , Dlugos Tamara , Artyomov Maxim N. , Dixit Vishwa Deep 
Published: September 2020

AbstractAging impairs the integrated immunometabolic responses which have evolved to maintain core body temperature in homeotherms to survive cold-stress, infections, and dietary restriction. Adipose tissue inflammation regulates the thermogenic stress response but how adipose tissue-resident cells instigate thermogenic failure in aged are unknown. Here, we define alterations in the adipose-resident immune system and identify that type 2 innate lymphoid cells (ILC2) are lost in aging. Restoration of ILC2 numbers in aged mice to levels seen in adults through IL-33 supplementation failed to rescue old mice from metabolic impairment and cold-induced lethality. Transcriptomic analyses revealed intrinsic defects in aged ILC2, and adoptive transfer of adult ILC2 are sufficient to protect old mice against cold. Thus, the functional defects in adipose ILC2 during aging drive thermogenic failure.One Sentence SummaryAge-related changes in adipose tissue drive reprogramming of ILC2 that leads to impaired cold tolerance
Optimal Control of Chlamydia Model with Vaccination
Authors: Odionyenma U. B. , Omame A. , Ukanwoke N.O. , Nometa I. 
Published: September 2020

AbstractThis paper presents an SVEIRT epidemiological model in the human population with Chlamydia trachomatis. The model incorporated the vaccination class and investigated the role played by some control strategies in the dynamics of the disease (Chlamydia tracomatis). The reproduction number which helps in determining the rate of spread of the disease, was calculated using the method proosed by van den Driessche and Watmough. The local and global stability of the equlibrium points where established, where it was observed that the model is locally asymptotically stable if the reproduction number is less than unity, and globally stable if a certain threshold value is greater than unity or the re-nfection rate is zero. The effect of the re-infection rate on the global stability suggests the exhibition of the phenomenon of backward bifurcation of the model. The backward bifurcation of the system was later studied, and it shows that backward bifurcation will occur if the value of the bifurcation parameter ‘a’ is positive. The optimal control of the model shows the effect of different strategies in the transmission dynamicsof the disease and the cost effectivenes of each control pair. It was observed that the treatment and control effort gives the most cost effective combinations and at the same time the highest rate of disease avertion when compared to other stratagies. Sensitivity analysis of the parameters as shown in model, shows parameters that have high impact on the chosen classes.
The more I know, the more I engage: consumer education's role in consumer engagement in the coffee shop context
Authors: Ornelas Sánchez Sidney A. , Vera Martínez Jorge 
Published: September 2020

PurposeThe present study examines the potential association between the company's efforts on consumer education and consumer engagement and addresses the implications of this link in strategic decision-making.Design/methodology/approachThe coffee shop industry serves as the context for testing the probable effect of education on creating more engaged consumers. To achieve this objective, regular coffee drinkers were asked to evaluate the education efforts of their favourite coffee shop and their level of engagement was assessed. Education and engagement were assessed using previously developed scales constituting a 32-item scale. The responses of 122 subjects were used in the analysis.FindingsConsumer education, both firm specific and market related, are found to be related to engagement within a coffee shop context. Findings might suggest alternative strategies within coffee shop brands to enhance their educational efforts to increasing their consumer's engagement levels, which might ultimately result in more loyal customers.Practical implicationsThe association between consumer education and consumer engagement is relevant when engagement is identified as a powerful predictor of several desired behavioural outcomes, such as satisfaction, word of mouth and loyalty. The possibility of education influencing consumer engagement might highlight an alternative strategy for companies pursuing higher engagement levels.Originality/valueAlthough both constructs, education and engagement, have been previously used to analyse a set of different phenomena, the present study is perhaps the first to address a potential correlation between the two.
How engaging leaders foster employees' work engagement
Authors: Rahmadani Vivi Gusrini , Schaufeli Wilmar B. , Stouten Jeroen 
Published: September 2020

PurposeThe current study investigates the mediating role of job resources (JRs) (i.e. person-–ob fit, value congruence, alignment, job control, use of skills, participation in decision-making, coworker support and performance feedback) and basic psychological need satisfaction at work (i.e. autonomy, relatedness, competence and meaningfulness) in the relationship between engaging leadership (EL) (i.e. inspiring, strengthening, empowering and connecting) and work engagement.Design/methodology/approachStructural equation analysis was used to test the mediation hypotheses, using a two-wave longitudinal design and an Indonesian sample of 412 employees from an agribusiness state-owned company.FindingsThe results show that EL at baseline 2017 (T1) predicts T1–T2 increase in work engagement (WE) directly, as well as indirectly through T1 JRs, and T1–T2 increase in basic psychological need satisfaction.Originality/valueThis research extends the job demands-resources (JD-R) model by showing the important role of ELfor fostering WE through increasing JRs and satisfying basic psychological needs at work.
The effect of authentic leadership and psychological capital on work engagement: the mediating role of job satisfaction
Authors: Wirawan Hillman , Jufri Muhammad , Saman Abdul 
Published: September 2020

PurposeThis study aims to investigate the effect of authentic leadership and psychological capital (PsyCap) on work engagement via job satisfaction by employing the job demands-resources (JD-R) model.Design/methodology/approachParticipants were 307 (52% male and 48% female) employees randomly recruited from a state-owned company in the eastern part of Indonesia. Most participants had completed an undergraduate degree with a mean age of 27.55 (SD = 7.89). The study employed a three-wave data collection technique to rule out any common method biases.FindingsThe results suggested that the theoretical model and empirical data showed a good fit (CMIN/DF = 2.19 and RMSEA = 0.06), indicating an indirect effect of authentic leadership and PsyCap on work engagement via job satisfaction. The effect of authentic leadership on work engagement was fully mediated by job satisfaction. In contrast, job satisfaction only partially mediated the relationship between PsyCap and work engagement.Research limitations/implicationsFirst, this study did not explore any further consequences of gender equality. Second, although the data have been compared with some existing studies, this study did not collect cross-cultural data from different countries. Lastly, the data were collected from a state-owned enterprise, which may limit generalisation to other organisations.Originality/valueThis study offered a new perspective by examining the implications of the JD-R model in the eastern part of Indonesia, where organisation culture is predominantly influenced by Buginese values. Furthermore, the inclusion of job satisfaction into the model added new information regarding the importance of mediating variables in explaining the indirect effect of job and personal resources.
The impact of a co-produced personality disorder training on staff burnout, knowledge and attitudes
Authors: Finamore Chloe , Rocca Fiammetta , Parker Jennie , Blazdell Julia , Dale Oliver 
Published: September 2020

Purpose
Mental health professionals working with patients with personality disorder are at risk of burnout. Burnout can adversely affect workforce retention and the delivery of high-quality care. The purpose of this paper is to investigate the impact of the three-day Knowledge and Understanding Framework (KUF) awareness-level personality disorder training on burnout, knowledge and attitudes in staff working in mental health settings.

Design/methodology/approach
A total of 253 mental health professionals attended the KUF training, delivered through a co-production model (i.e. co-delivered by a mental health professional and service user consultant with lived experience). Questionnaires were administered at pre- and post-training to assess changes in burnout symptoms and understanding, perceived capabilities and emotional reactions concerning personality disorder.

Findings
There were improvements in two burnout domains: decreases in emotional exhaustion (p = 0.009) and increases in personal accomplishment (p < 0.001) between pre-and post-training. Significant improvements were found in understanding, perceived capabilities and emotional reactions (p < 0.001).

Research limitations/implications
This evaluation is limited by a lack of a control group and long-term follow-up. Further research is required to investigate the sustainability of reductions in burnout for mental health professionals attending training and supervision structures.

Originality/value
KUF training may contribute to reductions in the high levels of burnout often experienced amongst staff working in mental health settings and could form a part of a broader strategy focussing on continued supervision and opportunities to integrate learning into practice.
The effect of crossovers on the stability of DNA origami type nanocarriers
Authors: Mogheiseh Maryam , Hasanzadeh Ghasemi Reza , Soheilifard Reza 
Published: September 2020

PurposeThe purpose of this paper is to compare the stability of the three nanocarriers created by DNA origami method with different positions and numbers of crossoversDesign/methodology/approachNanocarriers are attractive components among a variety of nanostructures created by DNA origami and can have numerous applications in mechanical and medical engineering. For this reason, the current study compares three nanotubes with different positions and numbers of crossovers created by DNA origami method that can be utilized as nanocarriers. To investigate the structures, the DNA nanocarriers are studied at the human body temperature 310 K. Molecular dynamics simulations are used for this study. For a quantitative analysis of DNA nanocarriers, the areas of three hexagons at three different sites in each of the nanotubes are investigated. The results indicate that the number and position of crossovers are among the significant factors in the structure stability of nanocarriers. The analyses also revealed that although adding crossovers in locations with fewer crossovers increase structural stability, the position of crossovers can have different effects on the stability. DNA origami-based nanocarriers can be implemented in drug delivery, allow the nanocargoes to pass various surfaces and act as filters for passing cargoes of different dimensions and chemical structures.FindingsThe results indicate that the number and position of crossovers are among the significant factors in the structure stability of nanocarriersOriginality/valueIn this paper, the stability of DNA origami nanocarriers with different positions and numbers of crossovers was investigated.