bluuebunny/crossref_metadata_2025 huggingface dataset:
Adipocyte deletion of the RNA binding protein HuR induces cardiac hypertrophy and fibrosis
Authors: Guarnieri Adrienne R. , Anthony Sarah R. , Gozdiff Anamarie , Green Lisa C. , Slone Sam , Nieman Michelle L. , Alam Perwez , Benoit Joshua B. , Kanisicak Onur , Tranter Michael
Published: January 2021

Adipose tissue continues to gain appreciation for its broad role as an endocrine organ, and disruptions in adipose tissue homeostasis plays a central role in cardiovascular physiology. We have previously shown that expression of the RNA binding protein HuR in adipose tissue mediates energy expenditure, but the potential cardiovascular impacts of this finding have not been explored. We show here that adipose tissue-specific deletion of HuR (Adipo-HuR-/-) is sufficient to induce the spontaneous development of cardiac hypertrophy and fibrosis. Hearts from Adipo-HuR-/-mice have increased left ventricular (LV) ejection fraction, rate of pressure generation, and LV posterior wall thickness that is accompanied by an increase in LV/body weight ratio and hypertrophic gene expression. Furthermore, Adipo-HuR-/-hearts display increased fibrosis by picrosirius red staining and periostin expression. To identify underlying mechanisms, we applied both RNA-seq and weighted gene co-expression network analysis (WGCNA) to define HuR-dependent changes in gene expression as well as significant relationships between adipose tissue gene expression and LV mass. RNA-seq results demonstrate a significant increase in pro-inflammatory gene expression in the subcutaneous white adipose tissue (scWAT) from Adipo-HuR-/-mice that is accompanied by an increase in serum levels of both TNF-α and IL-6. WGCNA identified a significant enrichment in inflammation, apoptosis/cell death, and vesicle-mediated transport genes among those whose expression most significantly associated with CVD in Adipo-HuR-/-. In conclusion, we demonstrate that the loss of HuR expression in adipose tissue promotes the development of cardiac hypertrophy and fibrosis, potentially through modulation of inflammation and vesicle-mediated transport in scWAT.

NEW AND NOTEWORTHY

This work demonstrates the spontaneous development of cardiac hypertrophy and fibrosis upon adipose tissue-specific deletion of the RNA binding protein HuR that appears to be mechanistically driven by HuR-dependent changes in inflammatory and extracellular vesicle transport mediating genes in the subcutaneous white adipose tissue. These results suggest that loss of HuR expression in adipose tissue in obesity, as demonstrated in mouse and humans by our group and others, may contribute to obesity-mediated CVD.
In VivoSubcellular Mass Spectrometry Enables Proteo-Metabolomic Single-cell Systems Biology in a Chordate Embryo Developing to a Normally Behaving Tadpole (X. laevis)
Authors: Lombard-Banek Camille , Li Jie , Portero Erika P. , Onjiko Rosemary M. , Singer Chase D. , Plotnick David , Al Shabeeb Reem Q. , Nemes Peter
Published: January 2021

We present the first example ofin vivohigh-resolution mass spectrometry (HRMS) for subcellular molecular systems biology of proteins and metabolites. With light microscopy, we identified the left-dorsal and left-ventral animal cells in cleavage-stage non-sentientXenopus laevisembryos. Using precision-translated fabricated microcapillaries, the subcellular content of each cell was double-probed, each time collecting <5% of cell volume (~10 nL) swiftly (<5 s/event). The proteins and metabolites were analyzed by custom-built ultrasensitive capillary electrophoresis electrospray ionization employing Orbitrap and time-of-flight HRMS. Label-free detection of ~150 metabolites (57 identified) and 738 proteins found proteo-metabolomic networks with differential quantitative activities between the cell types. Spatially and temporally scalable sampling the technology preserved the integrity of the analyzed cells, the neighboring cells, and the embryo. 95% of the analyzed embryos developed into sentient tadpoles that were indistinguishable from their wild-type siblings based on anatomy and visual function in a background color preference assay.
Dissecting the localization ofTilapia tilapinevirusin the brain of the experimentally infected Nile tilapia (Oreochromis niloticus)
Authors: Dinh-Hung Nguyen , Sangpo Pattiya , Kruangkum Thanapong , Kayansamruaj Pattanapon , Rung-ruangkijkrai Tilladit , Senapin Saengchan , Rodkhum Channarong , Dong Ha Thanh
Published: January 2021

Tilapia tilapinevirusor tilapia lake virus (TiLV) is an emerging virus that inflicts significant mortality on farmed tilapia globally. Previous studies reported detection of the virus in multiple organs of the infected fish; however, little is known about the in-depth localization of the virus in the central nervous system. Herein, we determined the distribution of TiLV in the entire brain of experimentally infected Nile tilapia.In situhybridization (ISH) using TiLV-specific probes revealed that the virus was broadly distributed throughout the brain. The strongest positive signals were dominantly detected in the forebrain (responsible for learning, appetitive behavior, and attention) and the hindbrain (involved in controlling locomotion and basal physiology). The permissive cell zones for viral infection were observed mostly to be along the blood vessels and the ventricles. This indicates that the virus may productively enter into the brain through the circulatory system and widen broad regions, possibly through the cerebrospinal fluid along the ventricles, and subsequently induce the brain dysfunction. Understanding the pattern of viral localization in the brain may help elucidate the neurological disorders of the diseased fish. This study revealed the distribution of TiLV in the whole infected brain, providing new insights into fish-virus interactions and neuropathogenesis.
Validation of binary non-targeted methods: mathematical framework and experimental designs
Authors: Uhlig Steffen , Nichani Kapil , Stoyke Manfred , Gowik Petra
Published: January 2021

Non-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

Mitochondrial 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

Various 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

The 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.
Genetic diversity, population structure and selection signature in Ethiopian Sorghum (Sorghum bicolor L. [Moench]) germplasm
Authors: Wondimu Zeleke , Dong Hongxu , Paterson Andrew H. , Worku Walelign , Bantte Kassahun
Published: January 2021

Ethiopia, the probable center of origin and diversity for sorghum (Sorghum bicolor L. [Moench]) and with unique eco-geographic features, possesses a large number of sorghum landraces that have not been well studied. Increased knowledge of this diverse germplasm through large-scale genomic characterization may contribute for understanding of evolutionary biology, and adequate use of these valuable resources from the center of origin. In this study, we characterized genetic diversity, population structure and selection signature in 304 sorghum accessions collected from diverse sorghum growing regions of Ethiopia using genotyping-by-sequencing (GBS). We identified a total of 108,107 high-quality single nucleotide polymorphism (SNPs) markers that were evenly distributed across the sorghum genome. The average gene diversity among accessions was high(He = 0.29). We detected a relatively low frequency of rare alleles (26%), highlighting the potential of this germplasm for subsequent allele mining studies through genome wide association studies (GWAS). While we found no evidence of genetic differentiation among administrative regions (FST = 0.02, p = 0.12), population structure and cluster analyses showed clear differentiation among six Ethiopian sorghum populations (FST = 0.28, p = 0.01) adapting to different environments. Analysis of SNP differentiation between the identified genetic groups revealed a total of 40 genomic regions carrying signatures of selection. These regions harbored candidate genes potentially involved in a variety of biological processes, including abiotic stress tolerance, pathogen defense and reproduction. Overall, a high level of untapped diversity for sorghum improvement remains available in Ethiopia, with patterns of diversity consistent with divergent selection on a range of adaptive characteristics.
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

Core 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

The 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

Ligand 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

We 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

A “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

LINE-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

Background

Autism 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.

Results

Using 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.

Conclusions

These 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.
Glass Containers’ Aura: The Gestalt of Material Milieu
Authors: Liu Lihong
Published: January 2021

Crystal glass containers as novel artefacts in the early modern period acted out their function of containment as miraculous material events. Focusing on glass containers used to contain and constitute Buddhist objects in China's Qing dynasty (1644–1911), this essay provides historical and critical views on issues of aura and containment. Primarily, it examines the modalities and experiences of container and containment as expressed in the Qing court's material, religious and political practices. In doing so, the essay highlights the fusional relationship between matter and form, while also apprehending the metamorphosis between image and object in processes of transmedial translation and transcultural crossing or dislocation. It argues that glass containers used to simulate, animate and amplify the ‘aura’ of devotional objects manifested more general religio‐political and intercultural phenomena at that time. Those phenomena in turn invite reflections on material objects' immaterial expressions, and vice versa, in terms of the interplay between formal schema and amorphous force.
Do Board Gender Quotas Benefit Minority Shareholders? An Illustration through Related‐Party Transactions
Authors: Nekhili Mehdi , Bennouri Moez , Nagati Haithem
Published: January 2021

We 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

Objectives

The 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.

Methods

From 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.

Results

Our 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).

Conclusion

Non‐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.
Cardiac arrhythmia during early‐week and mid‐week dialysis in hemodialysis patients
Authors: Vareesangthip Kornchanok , Yincharoen Picha , Winijkul Arjbordin , Chanchairujira Thawee
Published: January 2021

Data on cardiac arrhythmia and electrolyte changes during the dialysis cycle have been limited. Fifty‐two hemodialysis (HD) patients underwent 48‐h Holter monitoring during early‐week and mid‐week HD sessions. Pre‐HD and post‐HD blood samples were collected in both HD sessions. The 48‐h Holter data were divided into five phases: (1) 4‐h during the early‐week HD (HD1), (2) 12‐h post‐HD1, (3) 16‐h period between Phases 2 and 4 (used as the patient's baseline electrocardiography [ECG]), (4) 12‐h pre‐HD2 phase, and (5) 4‐h during the mid‐week HD (HD2). The patients' mean age was 68.54 ± 13.37 years. We found that the dialysate‐to‐serum[K] gradient and changes of S[K] were significantly higher in HD1 than in HD2, as well as changes of S[Mg]. There were no significant ECG changes during the 4‐h HD1 and HD2 when compared with the baseline ECG. Phase 2 of Holter ECG was the most common phase that showed significant changes (increased QT interval dispersion (QTD), increased ventricular events, increased number of premature ventricular contractions, ST elevation and ST depression), which was contributed from the dialysate[K] 2 mmol/L subgroup, but not the dialysate[K] 3 mmol/L subgroup. In the subgroup of patients with a high ultrafiltration rate (UFR; mean UFR ≥10 mL/kg/h), there were significantly increased ventricular events and ST‐segment changes in Phase 2. In conclusion, ECG changes were associated with the dialysis cycle, significantly in the 12‐h after early‐week HD sessions. These may be associated with low dialysate[K] or high dialysate‐to‐S[K] gradient, high ultrafiltration rate and duration of the interdialytic interval.
Whole‐body senescent cell clearance alleviates age‐related brain inflammation and cognitive impairment in mice
Authors: Ogrodnik Mikolaj , Evans Shane A. , Fielder Edward , Victorelli Stella , Kruger Patrick , Salmonowicz Hanna , Weigand Bettina M. , Patel Ayush D. , Pirtskhalava Tamar , Inman Christine L. , Johnson Kurt O. , Dickinson Stephanie L. , Rocha Azucena , Schafer Marissa J. , Zhu Yi , Allison David B. , von Zglinicki Thomas , LeBrasseur Nathan K. , Tchkonia Tamar , Neretti Nicola , Passos João F. , Kirkland James L. , Jurk Diana
Published: January 2021

Cellular senescence is characterized by an irreversible cell cycle arrest and a pro‐inflammatory senescence‐associated secretory phenotype (SASP), which is a major contributor to aging and age‐related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single‐nuclei and single‐cell RNA‐seq in the hippocampus from young and aged mice. We observed an age‐dependent increase in p16Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK‐ATTAC mice, in which p16Ink4a‐positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof‐of‐concept for senolytic interventions' being a potential therapeutic avenue for alleviating age‐associated cognitive impairment.
Salvage surgery for patients with residual disease after chemoradiation therapy for locally advanced cervical cancer: A systematic review on indication, complications, and survival
Authors: van Kol Kim G. G. , Ebisch Renée M. F. , Piek Jurgen M. J. , Zusterzeel Petra L. M. , Vergeldt Tineke F. M. , Bekkers Ruud L. M.
Published: January 2021

Introduction

Standard treatment for locally advanced cervical cancer is chemoradiation therapy. Treatment with chemoradiation therapy harbors a risk of local residual disease, which can be curatively treated with salvage surgery, but the risk of complications following surgical procedures in radiated tissue is not negligible. The presence of residual disease can be radiologically and/or histologically diagnosed. The objective of this study is to describe studies that report on salvage surgery for patients with locally advanced cervical cancer after primary treatment with chemoradiation therapy. Therefore, we assessed the method of determining the presence of residual disease, the risk of complications, and the survival rate after salvage surgery.

Material and methods

PubMed, EMBASE, and the Cochrane database were searched from inception up to 6 March 2020. Titles and abstracts were independently assessed by two researchers. Studies were eligible for inclusion when patients had locally advanced cervical cancer with radiologically suspected or histologically confirmed residual disease after chemoradiation therapy, diagnosed with a CT, MRI, or PET‐CT scan, or biopsy. Information on complications after salvage surgery and survival outcomes had to be reported. Methodological quality of the articles was independently assessed by two researchers with the Newcastle‐Ottawa scale.

Results

Of the 2963 screened articles, six studies were included, representing 220 women. A total of 175 patients were treated with salvage surgery, of whom 27%‐100% had residual disease on the surgery specimen. Of the 161 patients treated with salvage surgery based on positive biopsy results, 72%‐100% showed residual disease on the surgery specimen. Of the 44 patients treated with salvage surgery based on suspected residual disease on radiology, 27%‐48% showed residual disease on the salvage surgery specimen. A total of 105 complications were registered in 175 patients treated with salvage surgery. The overall survival rate after salvage surgery was 69% (mean follow‐up period of 24.9 months).

Conclusions

It is necessary to confirm residual disease by biopsy before performing salvage surgery in patients with locally advanced cervical cancer primarily treated with chemoradiation therapy. Salvage surgery only based on radiologically suspected residual disease should be avoided to prevent unnecessary surgery and complications.
Location of OprD porin in Pseudomonas aeruginosa clinical isolates
Authors: González‐Vázquez María Cristina , Rocha‐Gracia Rosa del Carmen , Carabarín‐Lima Alejandro , Bello‐López Elena , Huerta‐Romano Fernando , Martínez‐Laguna Ygnacio , Lozano‐Zarain Patricia
Published: January 2021

Multidrug‐resistant Pseudomonas aeruginosa is one of the main opportunistic pathogens causing severe infection. One of the mechanisms involved in the resistance to imipenem in clinical isolates is the loss of the OprD porin. Changes like substitutions, deletions, insertions, or mutations in the oprD gene can modify the conformation of OprD porin or inhibit its presence and generate resistance to carbapenems. The aim of this work was to obtain anti‐OprD polyclonal antibodies and to determine by both immunofluorescence microscopy (IFI) and Western blot assays, the presence of the OprD porin in resistant‐carbapenem P. aeruginosa strains with different changes in the oprD gene. Changes in the gene oprD were identified in clinical isolates of P. aeruginosa. When proteins were translated, several polymorphisms were found; however, these did not affect the presence of OprD porin (PCM25, PCM36, and PCM78). Also it was detected an insertion sequence ISPa1328 (PCM52) and a premature stop codon (PCM91), which inhibited the presence of the OprD porin. This study shows how changes in the oprD gene of P. aeruginosa clinical isolates affect the presence of the OprD porin detected by Western blot and indirect immunofluorescence assays using specific polyclonal anti‐OprD antibodies generated in this work.
Treatment strategy for laparoscopic hiatal hernia repair
Authors: Yano Fumiaki , Tsuboi Kazuto , Omura Nobuo , Hoshino Masato , Yamamoto Se R. , Akimoto Shunsuke , Masuda Takahiro , Mitsumori Norio , Ikegami Toru
Published: January 2021

Introduction

According to the anatomy‐function‐pathology classification, the recurrence rates of A2 and A3 hiatal hernia (HH) after laparoscopic fundoplication are higher than the rate of A1 HH. Therefore, we introduced mesh reinforcement for A2 and A3 cases. In addition, gastropexy was added to A3 cases. We present the strategy for HH repair.

Methods

In all, 537 patients (mean age 55.4 ± 16.7 years, 219 women) who underwent primary laparoscopic fundoplication for HH from January 1995 to October 2019 were included. They were divided into three groups by A factor (A1:A2:A3 = 296:156:85). Their clinical data were collected in a prospective fashion and retrospectively reviewed.

Results

The median age (years) of the patients in each group was A1:A2:A3 = 46:63:74 years, and age was directly proportional to the size of HH (P < 0.0001). The proportion of females was significantly higher in A3 than in other classes (P < 0.0001). Preoperative reflux esophagitis was severe in A2 (P < 0.0001) and operation time (min) was directly proportional to HH size (A1:A2:A3 = 135:167:193, P < 0.0001). The recurrence rate of conventional laparoscopic fundoplication was 15% (46/304), and it was higher for A2 and A3 than for A1 (P = 0.027). However, with reinforcement of the hiatus using a mesh and gastropexy, the recurrence rates decreased.

Conclusion

Combining mesh reinforcement and gastropexy may reduce the recurrence rate of para‐ and mixed‐type HH.
Acquired factor V inhibitor: a nation‐wide study of 38 patients
Authors: Goulenok Tiphaine , Vasco Claire , Faille Dorothée , Ajzenberg Nadine , De Raucourt Emmanuelle , Dupont Annabelle , Frere Corinne , James Chloé , Rabut Elodie , Rugeri Lucia , Schleinitz Nicolas , Sacré Karim , Papo Thomas ,   the RAVI study group
Published: January 2021

Acquired factor V inhibitor (AFVI) is an extremely rare disorder that may cause severe bleeding. To identify factors associated with bleeding risk in AFVI patients, a national, multicentre, retrospective study was made including all AFVI patients followed in 21 centres in France between 1988 and 2015. All patients had an isolated factor V (FV) deficiency <50% associated with inhibitor activity. Patients with constitutional FV deficiency and other causes of acquired coagulation FV deficiencies were excluded. The primary outcome was incident bleeding and factors associated with the primary outcome were identified. Thirty‐eight (74 [36–100] years, 42·1% females) patients with AFVI were analysed. Bleeding was reported in 18 (47·4%) patients at diagnosis and in three (7·9%) during follow‐up (7 [0·2–48.7] months). At diagnosis, FV was <10% in 31 (81·6%) patients. Bleeding at diagnosis was associated with a prolonged prothrombin time that strongly correlated with the AFVI level measured in plasma {r = 0·63, 95% confidence interval (CI) [0·36–0·80], P < 0·05}. Bleeding onset during follow‐up was associated with a slow AFVI clearance (P < 0·001). The corresponding receiver operating characteristics curve showed that AFVI clearance was predictive of bleeding onset with an AFVI clearance of seven months with a sensitivity of 100% (95% CI: 29–100) and a specificity of 86% (95% CI: 57–98, P = 0·02). Kaplan–Meier analysis showed that AFVI clearance >7 months increased the risk of bleeding by 8 (95% CI: [0·67–97], P = 0·075). Prothrombin time at diagnosis and time for clearance of FV inhibitor during follow‐up are both associated with bleeding in patients with AFVI.
Battling ingroup bias with effective intergroup leadership
Authors: Kershaw Christine , Rast David E. , Hogg Michael A. , van Knippenberg Daan
Published: January 2021

Intergroup conflict and bias often occur between subgroups nested within a superordinate group. In these situations, the leader of the superordinate group plays a key role, as an intergroup leader, in reducing conflict. To be effective, an intergroup leader should avoid (1) threatening the subgroups' distinctive identities, and (2) being viewed by one or both groups as ‘one of them’ rather than ‘one of us’. Intergroup leadership theory (Acad Manag Rev, 37, 2012a, 232) posits intergroup leaders can improve subgroup relations by promoting an intergroup relational identity. Two studies (Ns = 178 and 223) tested whether an out‐subgroup or in‐subgroup leader could improve intergroup attitudes, even among strong subgroup identifiers, by promoting either an intergroup relational identity or a collective identity. We hypothesized an interaction of these variables demonstrating the effectiveness of an intergroup relational identity message for an out‐subgroup leader in lessening ingroup bias, especially among strong subgroup identification. Our results, and a meta‐analytic summary across both studies (N = 401), supported our hypothesis and intergroup leadership theory, demonstrating an intergroup relational identity is an effective strategy for improving intergroup relations.
Does mining waste concentration in the soil interfere with leaf selection by Acromyrmex subterraneus (Formicidae)?
Authors: Nascimento Felipe dos Santos , Toledo Antônio Marcos Oliveira , Pimenta Maria de Paula , Resende Cristiano Ferrara de , Peixoto Paulo Henrique Pereira , Zimerer Arthur , Lopes Juliane Floriano Santos
Published: January 2021

Revegetation programs are proposed to recover the soil and biodiversity of disturbed sites, this being the case of the Rio Doce basin, Brazil. This region was hugely affected by a mining waste dam disruption, whose leakage on the soil altered its chemical and physical characteristics, and consequently the physiology and performance of plants. The expected alterations of the plants can make them more attractive for leaf‐cutting ants, as lower water content induces an increase of non‐structural carbohydrates. In this context, we evaluated whether Acromyrmex subterraneus workers differentiate among plants grown on soil with different mining waste concentrations. Leaf disks from plants grown in soil containing 0, 25, 50, 75, and 100% of mining waste were simultaneously offered to workers from laboratory ant colonies. The number of transported disks from each mining waste concentration was recorded until all disks of any concentration had been transported. Leaf selection assays were repeated after 30 days due to the novelty effect phenomenon. Leaf thickness, water, starch, and total soluble carbohydrates (TSC) contents were determined. Leaf disks from plants grown in soil with 100% of mining waste concentration were preferentially selected in both selection assays. Leaf thickness and water content were significantly lower in plants from the aforementioned treatment, while starch and TSC were higher. Results suggest that seedlings implanted in sites with high mining waste concentration are under high predation risk. Revegetation programs must measure the impact of leaf‐cutting ants as both herbivorous and soil ecosystem engineers, for the best management of these insects.

Abstract in Portuguese is available with online material