bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of binary non-targeted methods: mathematical framework and experimental designs
Authors: Uhlig Steffen , Nichani Kapil , Stoyke Manfred , Gowik Petra 
Published: January 2021

AbstractNon-targeted methods (NTMs) are being increasingly developed and adopted to detect food fraud and identify the authenticity of the food. Method validation is a critical step before bringing the NTMs to the routine to be assured of method performance and trust that its outcomes are reliable. However, the paucity of well structured and harmonized validation strategies has been one of the hurdles, withholding the exploitation of NTMs. This report aims to describe a validation framework for methods that involve binary classification, which are prevalent in non-targeted workflows. We foresee this work to contribute to filling the current gap in the provisions for NTM method validation; perhaps also push the dialogue further to collectively resolve existing challenges.
Mitochondrial oxidative stress drives IL-12/IL-18-induced IFN-γ production by CD4+T cells and is controlled by Fas
Authors: Rackov Gorjana , Zaniani Parinaz Tavakoli , del Pino Sara Colomo , Shokri Rahman , Alvarez-Mon Melchor , Martinez-A Carlos , Balomenos Dimitrios 
Published: January 2021

AbstractMitochondrial activation and mROS production are crucial for CD4+T cell responses and have a role in naïve cell signaling after TCR activation. However, little is known about their role in recall responses driven by cytokine signaling. Here, we found that mROS are required for IL-12 plus IL-18-driven production of IFN-γ, an essential cytokine in inflammatory and autoimmune disease development. In particular, memory-like cells obtained after activation-induced differentiation showed faster and augmented mROS accumulation and increased IFN-γ production in response to IL-12 plus IL-18 compared to naïve T cells. In contrast, mROS induction was similar in naïve and memory-like cells after TCR-dependent signaling. Taken together these results suggested that memory-like CD4+T cells treated by IL-12 plus IL-18 attained conditions for an extraordinary mROS-producing potential. mROS inhibition significantly downregulated the production of IFN-γ and the expression of CD44 activation marker, suggesting a direct mROS effect on the activation of memory-like T cells. Mechanistically, mROS was required for optimal activation of key signaling pathways that drive IFN-γ production after IL-12 plus IL-18 T cell stimulation, such as PKC-θ, AKT and STAT4 phosphorylation, and NF-κB activation. Notably, we identified increased mROS as key promoters of hyperactivation and IFN-γ overproduction in Fas-deficientlprmemory-like CD4+T cells compared to WT cells, following IL-12 plus IL-18 stimulation. mROS inhibition significantly reduced the population of disease-associated CD44hiCD62LlolprCD4+T cells and their IFN-γ production. These findings uncover a previously unidentified role for Fas in regulating mitochondrial ROS production by memory-like T cells. This apoptosis-independent Fas activity might contribute to the accumulation of CD44hiCD62LloCD4+T cells that produce increased IFN-γ levels inlprmice. Overall, our findings pinpoint mROS as central regulators of TCR-independent signaling, and support mROS pharmacological targeting to control aberrant immune responses in autoimmune-like disease.
Transcriptomic analysis reveals niche gene expression effects of beta-hydroxybutyrate in primary myotubes
Authors: Ruppert Philip M. M. , Hooiveld Guido J. E. J. , Hangelbroek Roland W. J. , Zeigerer Anja , Kersten Sander 
Published: January 2021

ABSTRACTVarious forms of fasting, including time-restricted feeding, alternate day fasting, and periodic fasting have shown promise in clinical and pre-clinical studies to normalize body weight, improve metabolic health, and protect against disease. Recent studies suggest that β-hydroxybutyrate (βOHB), a characteristic ketone body of the fasted metabolic state, acts as a potential signaling molecule mediating the beneficial effects of the various forms of fasting, potentially by acting as a histone deacetylase inhibitor. In the first part we investigated whether βOHB, in comparison to the well-established histone deacetylase inhibitor butyrate, influences cellular differentiationin vitro. In C2C12 myotubes, 3T3-L1 adipocytes, and THP-1 monocytes, millimolar concentrations of βOHB did not alter differentiation, as determined by gene expression and histological assessment, whereas equimolar concentrations of butyrate potently impaired differentiation in all cell types. RNA-sequencing revealed that unlike butyrate, βOHB minimally impacted gene expression in adipocytes, macrophages, and hepatocytes. However, in myocytes, βOHB upregulated genes involved in the TCA cycle and oxidative phosphorylation, while downregulating genes belonging to cytokine and chemokine signal transduction. Overall, our data do not support the notion that βOHB serves as a powerful signaling molecule regulating gene expression in adipocytes, macrophages and hepatocytes, but suggest that βOHB may act as a niche signaling molecule in muscle.
Immune phase transition under steroid treatment
Authors: Nayak Sonali Priyadarshini , Roy Susmita 
Published: January 2021

AbstractThe steroid hormone, Glucocorticoid (GC) is a well-known immunosuppressant that controls T cell-mediated adaptive immune response. In this work, we have developed a minimal kinetic network model of T-cell regulation connecting relevant experimental and clinical studies to quantitatively understand the long-term effects of GC on pro-inflammatory T-cell (Tpro) and anti-inflammatory T-cell (Tanti) dynamics. Due to the antagonistic relation between these two types of T-cells, their long-term steady-state population ratio helps us to characterize three classified immune-regulations: (i) weak ([Tpro]>[Tanti]); (ii) strong ([Tpro]<[Tanti]), and (iii) moderate ([Tpro] ∼ [Tanti]); holding the characteristic bistability). In addition to the differences in their long-term steady-state outcome, each immune-regulation shows distinct dynamical phases. In the pre-steady, a characteristic intermediate stationary phase is observed to develop only in the moderate regulation regime. In the medicinal field, the resting time in this stationary phase is distinguished as a clinical latent period. GC dose-dependent steady-state analysis shows an optimal level of GC to drive a phase-transition from the weak/auto-immune prone to the moderate regulation regime. Subsequently, the pre-steady state clinical latent period tends to diverge near that optimal GC level where [Tpro]: [Tanti] is highly balanced. The GC-optimized elongated stationary phase explains the rationale behind the requirement of long-term immune diagnostics, especially when long-term GC-based chemotherapeutics and other immunosuppressive drugs are administrated. Moreover, our study reveals GC sensitivity of clinical latent period which might serve as an early warning signal in the diagnosis of different immune phases and determining immune phase-wise steroid treatment.
An estimate of the deepest branches of the tree of life from ancient vertically-evolving genes
Authors: Moody Edmund R. R. , Mahendrarajah Tara A. , Dombrowski Nina , Clark James W. , Petitjean Celine , Offre Pierre , Szöllősi Gergely J. , Spang Anja , Williams Tom A. 
Published: January 2021

AbstractCore gene phylogenies provide a window into early evolution, but different gene sets and analytical methods have yielded substantially different views of the tree of life. Trees inferred from a small set of universal core genes have typically supported a long branch separating the archaeal and bacterial domains. By contrast, recent analyses of a broader set of non-ribosomal genes have suggested that Archaea may be less divergent from Bacteria, and that estimates of inter-domain distance are inflated due to accelerated evolution of ribosomal proteins along the inter-domain branch. Resolving this debate is key to determining the diversity of the archaeal and bacterial domains, the shape of the tree of life, and our understanding of the early course of cellular evolution. Here, we investigate the evolutionary history of the marker genes key to the debate. We show that estimates of a reduced Archaea-Bacteria (AB) branch length result from inter-domain gene transfers and hidden paralogy in the expanded marker gene set. By contrast, analysis of a broad range of manually curated marker gene datasets from an evenly sampled set of 700 Archaea and Bacteria reveal that current methods likely underestimate the AB branch length due to substitutional saturation and poor model fit; that the best-performing phylogenetic markers tend to support longer inter-domain branch lengths; and that the AB branch lengths of ribosomal and non-ribosomal marker genes are statistically indistinguishable. Furthermore, our phylogeny inferred from the 27 highest-ranked marker genes recovers a clade of DPANN at the base of the Archaea, and places CPR within Bacteria as the sister group to the Chloroflexota.
Expanding the marine range of the endangered black-capped petrelPterodroma hasitata: Occurrence in the northern Gulf of Mexico and conservation implications
Authors: Jodice Patrick G.R. , Michael Pamela E. , Gleason Jeffrey S. , Haney J. Christopher , Satgé Yvan G. 
Published: January 2021

ABSTRACTThe black-capped petrel (Pterodroma hasitata) is an endangered seabird endemic to the western north Atlantic. Although estimated at ~ 1,000 breeding pairs, only ~ 100 nests have been located at two sites in Haiti and three sites in the Dominican Republic. At sea, the species primarily occupies waters of the western Gulf Stream in the Atlantic and the Caribbean Sea. Due to limited data, there is currently not a consensus on the marine range of the species. There are several maps in use for the marine range of the species and these differ with respect to the north, south, and eastward extent of the range. None of these maps, however, includes the Gulf of Mexico. Here, we report on observations of black-capped petrels during two vessel-based survey efforts throughout the northern Gulf of Mexico from July 2010 - July 2011, and from April 2017 - September 2019. During the 558 days and 54.7 km of surveys from both efforts we tallied 40 black-capped petrels. Most observations occurred in the eastern Gulf, although birds were observed over much of the east-west and north-south footprint of the survey area. Predictive models indicated that habitat suitability for black-capped petrels was highest in areas associated with dynamic waters of the Loop Current, similar to habitat used along the western edge of the Gulf Stream in the western north Atlantic. We suggest that the range for black-capped petrels be modified to include the entire northern Gulf of Mexico although distribution may be more clumped in the eastern Gulf and patchier elsewhere. It remains unclear, however, which nesting areas are linked to the Gulf of Mexico.
A conserved regulatory module regulates receptor kinase signaling in immunity and development
Authors: DeFalco Thomas A. , Anne Pauline , James Sean R. , Willoughby Andrew , Johanndrees Oliver , Genolet Yasmine , Pullen Anne-Marie , Zipfel Cyril , Hardtke Christian S. , Nimchuk Zachary L. 
Published: January 2021

ABSTRACTLigand recognition by cell-surface receptors underlies development and immunity in both animals and plants. Modulating receptor signaling is critical for appropriate cellular responses but the mechanisms ensuring this are poorly understood. Here, we show that signaling by plant receptors for pathogen-associated molecular patterns (PAMPs) in immunity and CLAVATA3/EMBRYO SURROUNDING REGION-RELATED peptides (CLEp) in development employ a similar regulatory module. In the absence of ligand, signaling is dampened through association with specific type-2C protein phosphatases (PP2Cs). Upon activation, PAMP and CLEp receptors phosphorylate divergent cytosolic kinases, which, in turn, phosphorylate the phosphatases, thereby promoting their release from the receptor complexes. Our work reveals a regulatory circuit shared between immune and developmental receptor signaling, which may have broader important implications for plant receptor kinase-mediated signaling in general.
Evaluation and resolution of many challenges of neural spike-sorting: a new sorter
Authors: Hall Nathan J. , Herzfeld David J. , Lisberger Stephen G. 
Published: January 2021

AbstractWe evaluate existing spike sorters and present a new one that resolves many sorting challenges. The new sorter, called “full binary pursuit” or FBP, comprises multiple steps. First, it thresholds and clusters to identify the waveforms of all unique neurons in the recording. Second, it uses greedy binary pursuit to optimally recognize the spike events in the original voltages. Third, it resolves spike events that are described more accurately as the superposition of spikes from two other neurons. Fourth, it resolves situations where the recorded neurons drift in amplitude or across electrode contacts during a long recording session. Comparison with other sorters on real and simulated ground-truth datasets reveals many of the failure modes of spike sorters. We suggest a set of post-sorting analyses that can improve the veracity of neural recordings by minimizing the intrusion of those failure modes into analysis and interpretation of neural data.
A Universal Bacteriophage T4 Nanoparticle Platform to Design Multiplex SARS-CoV-2 Vaccine Candidates by CRISPR Engineering
Authors: Zhu Jingen , Ananthaswamy Neeti , Jain Swati , Batra Himanshu , Tang Wei-Chun , Lewry Douglass A. , Richards Michael L. , David Sunil A. , Kilgore Paul B. , Sha Jian , Drelich Aleksandra , Tseng Chien-Te K. , Chopra Ashok K. , Rao Venigalla B. 
Published: January 2021

AbstractA “universal” vaccine design platform that can rapidly generate multiplex vaccine candidates is critically needed to control future pandemics. Here, using SARS-CoV-2 pandemic virus as a model, we have developed such a platform by CRISPR engineering of bacteriophage T4. A pipeline of vaccine candidates were engineered by incorporating various viral components into appropriate compartments of phage nanoparticle structure. These include: expressible spike genes in genome, spike and envelope epitopes as surface decorations, and nucleocapsid proteins in packaged core. Phage decorated with spike trimers is found to be the most potent vaccine candidate in mouse and rabbit models. Without any adjuvant, this vaccine stimulated robust immune responses, both TH1 and TH2 IgG subclasses, blocked virus-receptor interactions, neutralized viral infection, and conferred complete protection against viral challenge. This new type of nanovaccine design framework might allow rapid deployment of effective phage-based vaccines against any emerging pathogen in the future.
LINE-1 Retrotransposon expression in cancerous, epithelial and neuronal cells revealed by 5’ single-cell RNA-Seq
Authors: McKerrow Wilson , Doudican Nicole , Frazzette Nicholas , Evans Shane A. , Rocha Azucena , Kagermazova Larisa , Sedivy John M. , Neretti Nicola , Carucci John , Boeke Jef D. , Fenyö David 
Published: January 2021

AbstractLINE-1 retrotransposons are sequences capable of copying themselves to new genomic loci via an RNA intermediate. New studies implicate LINE-1 in a range of diseases, especially in the context of aging, but without an accurate understanding of where and when LINE-1 is expressed, a full accounting of its role in health and disease is not possible. We therefore developed a method – 5’ scL1seq – that makes use of a widely available library preparation method (10x Genomics 5’ single cell RNA-seq) to measure LINE-1 expression in tens of thousands of single cells. We recapitulated the known pattern of LINE-1 expression in tumors – present in cancer cells, absent from immune cells – and identified hitherto undescribed LINE-1 expression in human epithelial cells and mouse hippocampal neurons. In both cases, we saw a modest increase with age, supporting recent research connecting LINE-1 to age related diseases.
DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder
Authors: Bam Sophia , Buchanan Erin , Mahony Caitlyn , O’Ryan Colleen 
Published: January 2021

AbstractBackgroundAutism Spectrum Disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including canonical mitochondrial pathways. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the aetiology of ASD. We examined the relationship between DNA methylation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), an essential transcriptional regulator of mitochondrial homeostasis, and mitochondrial dysfunction in an ASD cohort of South African children.ResultsUsing targeted Next Generation bisulfite sequencing, we found 12 highly variable CpG sites in PGC-1α that were significantly differentially methylated (p<0.05) between ASD (n = 55) and controls (n = 44). In ASD, eight CpG sites were hypermethylated in the PGC-1α promotor with a putative binding site for CAMP response binding element 1 (CREB1) spanning one of these CpG sites (p = 1 × 10−6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1α promoter. There was a positive correlation between methylation at PGC-1α at CpG#1 and mtDNA copy number (Spearman’s r = 0.2, n = 49, p = 0.04) in ASD, but a negative correlation between methylation at PGC-1α at CpG#4 promoter and mtDNA copy number in controls (Spearman’s r = −0.4, n = 42, p = 0.045). While there was no relationship between mtDNA deletions and PGC-1α methylation in ASD, mtDNA deletions correlated negatively with methylation at PGC-1α at CpG#4 (Spearman’s r = −0.4, n = 42, p = 0.032) in controls. Furthermore, levels of urinary organic acids associated with mitochondrial dysfunction correlated significantly (p<0.05) with DNA methylation at PGC-1α CpG#1 and mtDNA copy number in ASD (n= 20) and controls (n= 13) with many of these metabolites involved in altered redox homeostasis and neuroendocrinology.ConclusionsThese data show an association between PGC-1α promoter methylation, elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored link between DNA methylation and mitochondrial dysfunction in ASD.
Do Board Gender Quotas Benefit Minority Shareholders? An Illustration through Related‐Party Transactions
Authors: Nekhili Mehdi , Bennouri Moez , Nagati Haithem 
Published: January 2021

AbstractWe use a sample of French firms over the period 2001–2017 to investigate the relationship between board gender diversity and related‐party transactions (RPTs). Although some of these transactions are efficient, RPTs are usually perceived negatively by outsiders because of the existence of conflict‐of‐interest transactions deemed to be value‐destroying. Based on agency theory and managerial power theory, we argue that female directors have the ability and motivation to challenge managers’ use of RPTs. Consistently with this argument, we find that board gender diversity negatively correlates with the number of reported RPTs. This negative correlation is driven by female directors involved in the board's monitoring duties (female independent directors and members of the audit committee). However, because they are less likely to be able to challenge managers, female inside directors do not affect the occurrence of RPTs. In January 2011, the French regulator enacted a gender quota law resulting in a significant increase in female board representativeness. We find that the marginal effect after enacting the gender quota law on the number of reported RPTs is negative for the proportion of female independent directors and female audit committee members, and positive for female inside directors.
Factors affecting the non‐urgent consultations in the emergency department of a tertiary hospital in the Philippines: A cross‐sectional study
Authors: Jimenez Ma Lourdes CD , Manzanera Rafael , Carascal Mark B , Figueras Marlouie DL , Wong John Q , Moya Diego , Mira Jose J 
Published: January 2021

AbstractObjectivesThe non‐standard emergency medicine services and the limited utilisation of primary care providers in the Philippines may contribute towards the ED being a preferred area for patients with non‐urgent conditions. Our study aims to determine the factors associated with non‐urgent consultations in the ED of a tertiary hospital in the Philippines.MethodsFrom 7 January to 15 February 2020, we surveyed non‐urgent ED patients (n = 757) presenting to a tertiary hospital in the Philippines. We evaluated the data using descriptive statistics, while chi‐squared and multivariate analyses versus urgent ED patients (n = 281) were used to show the association of factors.ResultsOur recruited non‐urgent patients were mostly 21–40 years old (n = 576 [76%]), single (n = 437 [58%]), with full‐time employment (n = 654 [86%]), have Health Maintenance Organization coverage (n = 684 [90%]), self‐referred (n = 498 [66%]), and have private means of getting to ED (n = 414 [55%]). They had moderate scores of social support‐seeking behaviours (mean 3.92/5; 95% confidence interval [CI] 3.88–3.96), health literacy (mean 3.58/5; 95% CI 3.56–3.61), self‐efficacy (mean 3.09/5; 95% CI 3.56–3.61), whereas their ED access score (mean 4.10/5; 95% CI 4.06–4.14) was high. They had moderate self‐assessed severity (mean 3.75/6; 95% CI 3.70–3.80), urgency (mean 3.83/6; 95% CI 3.78–3.88), and anxiety (mean 3.88/6; 95% CI 3.83–3.93) scores and high ED satisfaction rating (mean 4.73/6; 95% CI 4.69–4.77). They mostly had digestive (n = 203 [26.8%]) and infection‐related (n = 172 [22.7%]) chief complaints and final diagnoses (n = 198 [26.2%] and n = 145 [19.2%], respectively), without previous consultations (n = 577 [76%]), and eventually discharged (n = 755 [99%]). Our urgent patients had similar characteristics, but with higher assessed patient severity, urgency, anxiety and satisfaction with ED services (P < 0.001).ConclusionNon‐urgent consultations in ED are attributed to multiple factors encompassing socio‐demographic, socio‐economic and psychosocial dimensions. These factors must be considered in improving the current healthcare management system for the appropriate utilisation of ED in the Philippines.