bluuebunny/crossref_metadata_2025 huggingface dataset:
SRF is a nonhistone methylation target of KDM2B and SET7 in the regulation of skeletal muscle differentiation
Authors: Kwon Duk-Hwa , Kang Joo-Young , Joung Hosouk , Kim Ji-Young , Jeong Anna , Min Hyun-Ki , Shin Sera , Lee Yun-Gyeong , Kim Young-Kook , Seo Sang-Beom , Kook Hyun
Published: February 2021

The demethylation of histone lysine residues, one of the most important modifications in transcriptional regulation, is associated with various physiological states. KDM2B is a demethylase of histones H3K4, H3K36, and H3K79 and is associated with the repression of transcription. Here, we present a novel mechanism by which KDM2B demethylates serum response factor (SRF) K165 to negatively regulate muscle differentiation, which is counteracted by the histone methyltransferase SET7. We show that KDM2B inhibited skeletal muscle differentiation by inhibiting the transcription of SRF-dependent genes. Both KDM2B and SET7 regulated the balance of SRF K165 methylation. SRF K165 methylation was required for the transcriptional activation of SRF and for the promoter occupancy of SRF-dependent genes. SET7 inhibitors blocked muscle cell differentiation. Taken together, these data indicate that SRF is a nonhistone target of KDM2B and that the methylation balance of SRF as maintained by KDM2B and SET7 plays an important role in muscle cell differentiation.
Cannabinoid CB1 receptor in dorsal telencephalic glutamatergic neurons drives overconsumption of palatable food and obesity
Authors: Ruiz de Azua Inigo , Martin-Garcia Elena , Domingo-Rodriguez Laura , Aparisi Rey Alejandro , Pascual Cuadrado Diego , Islami Larglinda , Turunen Petri , Remmers Floortje , Lutz Beat , Maldonado Rafael
Published: February 2021

Palatable food can promote overfeeding beyond homeostatic requirements, thereby constituting a major risk to obesity. Here, the lack of cannabinoid type 1 receptor (CB1) in dorsal telencephalic glutamatergic neurons (Glu-CB1-KO) abrogated the overconsumption of palatable food and the development of obesity. On low-fat diet, no genotype differences were observed. However, under palatable food conditions, Glu-CB1-KO mice showed decreased body weight and food intake. Notably, Glu-CB1-KO mice were protected from alterations in the reward system after high-fat diet feeding. Interestingly, obese wild-type mice showed a superior olfactory detection as compared to mutant mice, suggesting a link between overconsumption of palatable food and olfactory function. Reconstitution of CB1 expression in olfactory cortex in high-fat diet-fed Glu-CB1-KO mice using viral gene delivery partially reversed the lean phenotype concomitantly with improved odor perception. These findings indicate that CB1 in cortical glutamatergic neurons regulates hedonic feeding, whereby a critical role of the olfactory cortex was uncovered as an underlying mechanism.
Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis
Authors: Xu Sha , Tao Hui , Cao Wei , Cao Li , Lin Yan , Zhao Shi-Min , Xu Wei , Cao Jing , Zhao Jian-Yuan
Published: February 2021

In addition to their use in relieving the symptoms of various diseases, ketogenic diets (KDs) have also been adopted by healthy individuals to prevent being overweight. Herein, we reported that prolonged KD exposure induced cardiac fibrosis. In rats, KD or frequent deep fasting decreased mitochondrial biogenesis, reduced cell respiration, and increased cardiomyocyte apoptosis and cardiac fibrosis. Mechanistically, increased levels of the ketone body β-hydroxybutyrate (β-OHB), an HDAC2 inhibitor, promoted histone acetylation of the Sirt7 promoter and activated Sirt7 transcription. This in turn inhibited the transcription of mitochondrial ribosome-encoding genes and mitochondrial biogenesis, leading to cardiomyocyte apoptosis and cardiac fibrosis. Exogenous β-OHB administration mimicked the effects of a KD in rats. Notably, increased β-OHB levels and SIRT7 expression, decreased mitochondrial biogenesis, and increased cardiac fibrosis were detected in human atrial fibrillation heart tissues. Our results highlighted the unknown detrimental effects of KDs and provided insights into strategies for preventing cardiac fibrosis in patients for whom KDs are medically necessary.
Author Correction: Blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia: results of the RIALTO trial, an expanded access study
Authors: Locatelli Franco , Zugmaier Gerhard , Mergen Noemi , Bader Peter , Jeha Sima , Schlegel Paul-Gerhardt , Bourquin Jean-Pierre , Handgretinger Rupert , Brethon Benoit , Rossig Claudia , Chen-Santel Christiane
Published: February 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41408-021-00413-7.
Dynamic sex chromosome expression in Drosophila male germ cells
Authors: Mahadevaraju Sharvani , Fear Justin M. , Akeju Miriam , Galletta Brian J. , Pinheiro Mara M. L. S. , Avelino Camila C. , Cabral-de-Mello Diogo C. , Conlon Katie , Dell’Orso Stafania , Demere Zelalem , Mansuria Kush , Mendonça Carolina A. , Palacios-Gimenez Octavio M. , Ross Eli , Savery Max , Yu Kevin , Smith Harold E. , Sartorelli Vittorio , Yang Haiwang , Rusan Nasser M. , Vibranovski Maria D. , Matunis Erika , Oliver Brian
Published: February 2021

Given their copy number differences and unique modes of inheritance, the evolved gene content and expression of sex chromosomes is unusual. In many organisms the X and Y chromosomes are inactivated in spermatocytes, possibly as a defense mechanism against insertions into unpaired chromatin. In addition to current sex chromosomes, Drosophila has a small gene-poor X-chromosome relic (4th) that re-acquired autosomal status. Here we use single cell RNA-Seq on fly larvae to demonstrate that the single X and pair of 4th chromosomes are specifically inactivated in primary spermatocytes, based on measuring all genes or a set of broadly expressed genes in testis we identified. In contrast, genes on the single Y chromosome become maximally active in primary spermatocytes. Reduced X transcript levels are due to failed activation of RNA-Polymerase-II by phosphorylation of Serine 2 and 5.
Quantifying population contact patterns in the United States during the COVID-19 pandemic
Authors: Feehan Dennis M. , Mahmud Ayesha S.
Published: February 2021

SARS-CoV-2 is transmitted primarily through close, person-to-person interactions. Physical distancing policies can control the spread of SARS-CoV-2 by reducing the amount of these interactions in a population. Here, we report results from four waves of contact surveys designed to quantify the impact of these policies during the COVID-19 pandemic in the United States. We surveyed 9,743 respondents between March 22 and September 26, 2020. We find that interpersonal contact has been dramatically reduced in the US, with an 82% (95%CI: 80%–83%) reduction in the average number of daily contacts observed during the first wave compared to pre-pandemic levels. However, we find increases in contact rates over the subsequent waves. We also find that certain demographic groups, including people under 45 and males, have significantly higher contact rates than the rest of the population. Tracking these changes can provide rapid assessments of the impact of physical distancing policies and help to identify at-risk populations.
Carbon fractions in the world’s dead wood
Authors: Martin Adam R. , Domke Grant M. , Doraisami Mahendra , Thomas Sean C.
Published: February 2021

A key uncertainty in quantifying dead wood carbon (C) stocks—which comprise ~8% of total forest C pools globally—is a lack of accurate dead wood C fractions (CFs) that are employed to convert dead woody biomass into C. Most C estimation protocols utilize a default dead wood CF of 50%, but live tree studies suggest this value is an over-estimate. Here, we compile and analyze a global database of dead wood CFs in trees, showing that dead wood CFs average 48.5% across forests, deviating significantly from 50%, and varying systematically among biomes, taxonomic divisions, tissue types, and decay classes. Utilizing data-driven dead wood CFs in tropical forests alone may correct systematic overestimates in dead wood C stocks of ~3.0 Pg C: an estimate approaching nearly the entire dead wood C pool in the temperate forest biome. We provide for the first time, robust empirical dead wood CFs to inform global forest C estimation.
Particle number-based trophic transfer of gold nanomaterials in an aquatic food chain
Authors: Abdolahpur Monikh Fazel , Chupani Latifeh , Arenas-Lago Daniel , Guo Zhiling , Zhang Peng , Darbha Gopala Krishna , Valsami-Jones Eugenia , Lynch Iseult , Vijver Martina G. , van Bodegom Peter M. , Peijnenburg Willie J.G.M.
Published: February 2021

Analytical limitations considerably hinder our understanding of the impacts of the physicochemical properties of nanomaterials (NMs) on their biological fate in organisms. Here, using a fit-for-purpose analytical workflow, including dosing and emerging analytical techniques, NMs present in organisms are characterized and quantified across an aquatic food chain. The size and shape of gold (Au)-NMs are shown to control the number of Au-NMs attached to algae that were exposed to an equal initial concentration of 2.9 × 1011 particles mL−1. The Au-NMs undergo size/shape-dependent dissolution and agglomeration in the gut of the daphnids, which determines the size distribution of the NMs accumulated in fish. The biodistribution of NMs in fish tissues (intestine, liver, gills, and brain) also depends on NM size and shape, although the highest particle numbers per unit of mass are almost always present in the fish brain. The findings emphasize the importance of physicochemical properties of metallic NMs in their biotransformations and tropic transfers.
Molecular mechanism for rapid autoxidation in α-pinene ozonolysis
Authors: Iyer Siddharth , Rissanen Matti P. , Valiev Rashid , Barua Shawon , Krechmer Jordan E. , Thornton Joel , Ehn Mikael , Kurtén Theo
Published: February 2021

Aerosol affects Earth’s climate and the health of its inhabitants. A major contributor to aerosol formation is the oxidation of volatile organic compounds. Monoterpenes are an important class of volatile organic compounds, and recent research demonstrate that they can be converted to low-volatility aerosol precursors on sub-second timescales following a single oxidant attack. The α-pinene + O3 system is particularly efficient in this regard. However, the actual mechanism behind this conversion is not understood. The key challenge is the steric strain created by the cyclobutyl ring in the oxidation products. This strain hinders subsequent unimolecular hydrogen-shift reactions essential for lowering volatility. Using quantum chemical calculations and targeted experiments, we show that the excess energy from the initial ozonolysis reaction can lead to novel oxidation intermediates without steric strain, allowing the rapid formation of products with up to 8 oxygen atoms. This is likely a key route for atmospheric organic aerosol formation.
Programmable human histone phosphorylation and gene activation using a CRISPR/Cas9-based chromatin kinase
Authors: Li Jing , Mahata Barun , Escobar Mario , Goell Jacob , Wang Kaiyuan , Khemka Pranav , Hilton Isaac B.
Published: February 2021

Histone phosphorylation is a ubiquitous post-translational modification that allows eukaryotic cells to rapidly respond to environmental stimuli. Despite correlative evidence linking histone phosphorylation to changes in gene expression, establishing the causal role of this key epigenomic modification at diverse loci within native chromatin has been hampered by a lack of technologies enabling robust, locus-specific deposition of endogenous histone phosphorylation. To address this technological gap, here we build a programmable chromatin kinase, called dCas9-dMSK1, by directly fusing nuclease-null CRISPR/Cas9 to a hyperactive, truncated variant of the human MSK1 histone kinase. Targeting dCas9-dMSK1 to human promoters results in increased target histone phosphorylation and gene activation and demonstrates that hyperphosphorylation of histone H3 serine 28 (H3S28ph) in particular plays a causal role in the transactivation of human promoters. In addition, we uncover mediators of resistance to the BRAF V600E inhibitor PLX-4720 in human melanoma cells using genome-scale screening with dCas9-dMSK1. Collectively, our findings enable a facile way to reshape human chromatin using CRISPR/Cas9-based epigenome editing and further define the causal link between histone phosphorylation and human gene activation.
Author Correction: Inhibitory neurotransmission drives endocannabinoid degradation to promote memory consolidation
Authors: Dubois Christophe J. , Fawcett-Patel Jessica , Katzman Paul A. , Liu Siqiong June
Published: February 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21329-7.
Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles
Authors: Brouwer Philip J. M. , Antanasijevic Aleksandar , de Gast Marlon , Allen Joel D. , Bijl Tom P. L. , Yasmeen Anila , Ravichandran Rashmi , Burger Judith A. , Ozorowski Gabriel , Torres Jonathan L. , LaBranche Celia , Montefiori David C. , Ringe Rajesh P. , van Gils Marit J. , Moore John P. , Klasse Per Johan , Crispin Max , King Neil P. , Ward Andrew B. , Sanders Rogier W.
Published: February 2021

The HIV-1 envelope glycoprotein trimer is poorly immunogenic because it is covered by a dense glycan shield. As a result, recombinant Env glycoproteins generally elicit inadequate antibody levels that neutralize clinically relevant, neutralization-resistant (Tier-2) HIV-1 strains. Multivalent antigen presentation on nanoparticles is an established strategy to increase vaccine-driven immune responses. However, due to nanoparticle instability in vivo, the display of non-native Env structures, and the inaccessibility of many neutralizing antibody (NAb) epitopes, the effects of nanoparticle display are generally modest for Env trimers. Here, we generate two-component self-assembling protein nanoparticles presenting twenty SOSIP trimers of the clade C Tier-2 genotype 16055. We show in a rabbit immunization study that these nanoparticles induce 60-fold higher autologous Tier-2 NAb titers than the corresponding SOSIP trimers. Epitope mapping studies reveal that the presentation of 16055 SOSIP trimers on these nanoparticle focuses antibody responses to an immunodominant apical epitope. Thus, these nanoparticles are a promising platform to improve the immunogenicity of Env trimers with apex-proximate NAb epitopes.
Elucidating the complex organization of neural micro-domains in the locust Schistocerca gregaria using dMRI
Authors: Shahid Syed Salman , Kerskens Christian M. , Burrows Malcolm , Witney Alice G.
Published: February 2021

To understand brain function it is necessary to characterize both the underlying structural connectivity between neurons and the physiological integrity of these connections. Previous research exploring insect brain connectivity has typically used electron microscopy techniques, but this methodology cannot be applied to living animals and so cannot be used to understand dynamic physiological processes. The relatively large brain of the desert locust,Schistercera gregaria(Forksȧl) is ideal for exploring a novel methodology; micro diffusion magnetic resonance imaging (micro-dMRI) for the characterization of neuronal connectivity in an insect brain. The diffusion-weighted imaging (DWI) data were acquired on a preclinical system using a customised multi-shell diffusion MRI scheme optimized to image the locust brain. Endogenous imaging contrasts from the averaged DWIs and Diffusion Kurtosis Imaging (DKI) scheme were applied to classify various anatomical features and diffusion patterns in neuropils, respectively. The application of micro-dMRI modelling to the locust brain provides a novel means of identifying anatomical regions and inferring connectivity of large tracts in an insect brain. Furthermore, quantitative imaging indices derived from the kurtosis model that include fractional anisotropy (FA), mean diffusivity (MD) and kurtosis anisotropy (KA) can be extracted. These metrics could, in future, be used to quantify longitudinal structural changes in the nervous system of the locust brain that occur due to environmental stressors or ageing.
Water mediated growth of oriented single crystalline SrCO3 nanorod arrays on strontium compounds
Authors: Hong Junsung , Heo Su Jeong , Singh Prabhakar
Published: February 2021

Morphology-controlled strontianite nanostructures have attracted interest in various fields, such as electrocatalyst and photocatalysts. Basic additives in aqueous strontium solutions is commonly used in controlling strontianite nanostructures. Here, we show that trace water also serves an important role in forming and structuring vertically oriented strontianite nanorod arrays on strontium compounds. Using in situ Raman spectroscopy, we monitored the structural evolution from hydrated strontium to strontianite nanorods, demonstrating the epitaxial growth by vapor–liquid–solid mechanism. Water molecules cause not only the exsolution of Sr liquid droplets on the surface but also the uptake of airborne CO2 followed by its ionization to CO32−. The existence of intermediate SrHO+–OCO22− phase indicates the interaction of CO32− with SrOH+ in Sr(OH)x(H2O)y cluster to orient strontianite crystals. X-ray diffraction simulation and transmission electron microscopy identify the preferred-orientation plane of the 1D nanostructures as the (002) plane, i.e., the growth along the c-axis. The anisotropic growth habit is found to be affected by the kinetics of carbonation. This study paves the way for designing and developing 1D architecture of alkaline earth metal carbonates by a simple method without external additives at room temperature.
The association between plant-based dietary patterns and risk of breast cancer: a case–control study
Authors: Rigi Somaye , Mousavi Seyed Mohammad , Benisi-Kohansal Sanaz , Azadbakht Leila , Esmaillzadeh Ahmad
Published: February 2021

Limited data are available, linking the plant-based diets to breast cancer (BC). We examined the association of overall plant-based diet index (PDI), hypothesized healthful (hPDI) and unhealthful versions of a plant-based diet index (uPDI) with BC in Iranian women. This population-based case–control study included 350 cases with newly diagnosed BC and 700 age-matched apparently healthy controls. We collected dietary data using a validated, Willett-format semi-quantitative food frequency questionnaire. Using these data, we generated a PDI by dedicating positive scores to plant foods, and reverse scores to animal foods, hPDI by assigning positive scores to healthy plant foods and reverse scores to less healthy plant foods and animal foods, and finally uPDI in which positive scores were assigned to less healthy plant foods and reverse scores to healthy plant foods and animal foods. After controlling for potential confounders, individuals in the highest quartile of PDI had 67% lower odds of BC than those in the lowest quartile (OR 0.33; 95% CI 0.22–0.50). Individuals with the greatest adherence to hPDI were 36% less likely to have BC than those with the lowest adherence, in the fully adjusted model (OR 0.64; 95% CI 0.43–0.94). In terms of uPDI, women in the top quartile had a 2.23 times greater chance of BC than those in the bottom quartile (OR 2.23; 95% CI 1.48–3.36). Greater adherence to PDI and hPDI was inversely associated with the risk of BC, whereas uPDI was associated with an increased risk.
High prevalence of antibiotic resistance in commensal Escherichia coli from healthy human sources in community settings
Authors: Nji Emmanuel , Kazibwe Joseph , Hambridge Thomas , Joko Carolyn Alia , Larbi Amma Aboagyewa , Damptey Lois Afua Okyerewaa , Nkansa-Gyamfi Nana Adoma , Stålsby Lundborg Cecilia , Lien La Thi Quynh
Published: February 2021

Antibiotic resistance is a global health crisis that requires urgent action to stop its spread. To counteract the spread of antibiotic resistance, we must improve our understanding of the origin and spread of resistant bacteria in both community and healthcare settings. Unfortunately, little attention is being given to contain the spread of antibiotic resistance in community settings (i.e., locations outside of a hospital inpatient, acute care setting, or a hospital clinic setting), despite some studies have consistently reported a high prevalence of antibiotic resistance in the community settings. This study aimed to investigate the prevalence of antibiotic resistance in commensal Escherichia coli isolates from healthy humans in community settings in LMICs. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we synthesized studies conducted from 1989 to May 2020. A total of 9363 articles were obtained from the search and prevalence data were extracted from 33 articles and pooled together. This gave a pooled prevalence of antibiotic resistance (top ten antibiotics commonly prescribed in LMICs) in commensal E. coli isolates from human sources in community settings in LMICs of: ampicillin (72% of 13,531 isolates, 95% CI: 65–79), cefotaxime (27% of 6700 isolates, 95% CI: 12–44), chloramphenicol (45% of 7012 isolates, 95% CI: 35–53), ciprofloxacin (17% of 10,618 isolates, 95% CI: 11–25), co-trimoxazole (63% of 10,561 isolates, 95% CI: 52–73), nalidixic acid (30% of 9819 isolates, 95% CI: 21–40), oxytetracycline (78% of 1451 isolates, 95% CI: 65–88), streptomycin (58% of 3831 isolates, 95% CI: 44–72), tetracycline (67% of 11,847 isolates, 95% CI: 59–74), and trimethoprim (67% of 3265 isolates, 95% CI: 59–75). Here, we provided an appraisal of the evidence of the high prevalence of antibiotic resistance by commensal E. coli in community settings in LMICs. Our findings will have important ramifications for public health policy design to contain the spread of antibiotic resistance in community settings. Indeed, commensal E. coli is the main reservoir for spreading antibiotic resistance to other pathogenic enteric bacteria via mobile genetic elements.
A personalized and evolutionary algorithm for interpretable EEG epilepsy seizure prediction
Authors: Pinto Mauro. F. , Leal Adriana , Lopes Fábio , Dourado António , Martins Pedro , Teixeira César A.
Published: February 2021

Seizure prediction may improve the quality of life of patients suffering from drug-resistant epilepsy, which accounts for about 30% of the total epileptic patients. The pre-ictal period determination, characterized by a transitional stage between normal brain activity and seizure, is a critical step. Past approaches failed to attain real-world applicability due to lack of generalization capacity. More recently, deep learning techniques may outperform traditional classifiers and handle time dependencies. However, despite the existing efforts for providing interpretable insights, clinicians may not be willing to make high-stake decisions based on them. Furthermore, a disadvantageous aspect of the more usual seizure prediction pipeline is its modularity and significant independence between stages. An alternative could be the construction of a search algorithm that, while considering pipeline stages’ synergy, fine-tunes the selection of a reduced set of features that are widely used in the literature and computationally efficient. With extracranial recordings from 19 patients suffering from temporal-lobe seizures, we developed a patient-specific evolutionary optimization strategy, aiming to generate the optimal set of features for seizure prediction with a logistic regression classifier, which was tested prospectively in a total of 49 seizures and 710 h of continuous recording and performed above chance for 32% of patients, using a surrogate predictor. These results demonstrate the hypothesis of pre-ictal period identification without the loss of interpretability, which may help understanding brain dynamics leading to seizures and improve prediction algorithms.
Overcoming Pavlovian bias in semantic space
Authors: Ereira Sam , Pujol Marine , Guitart-Masip Marc , Dolan Raymond J. , Kurth-Nelson Zeb
Published: February 2021

Action is invigorated in the presence of reward-predicting stimuli and inhibited in the presence of punishment-predicting stimuli. Although valuable as a heuristic, this Pavlovian bias can also lead to maladaptive behaviour and is implicated in addiction. Here we explore whether Pavlovian bias can be overcome through training. Across five experiments, we find that Pavlovian bias is resistant to unlearning under most task configurations. However, we demonstrate that when subjects engage in instrumental learning in a verbal semantic space, as opposed to a motoric space, not only do they exhibit the typical Pavlovian bias, but this Pavlovian bias diminishes with training. Our results suggest that learning within the semantic space is necessary, but not sufficient, for subjects to unlearn their Pavlovian bias, and that other task features, such as gamification and spaced stimulus presentation may also be necessary. In summary, we show that Pavlovian bias, whilst robust, is susceptible to change with experience, but only under specific environmental conditions.
Steroid receptor coactivator 3 (SRC-3/AIB1) is enriched and functional in mouse and human Tregs
Authors: Nikolai Bryan C. , Jain Prashi , Cardenas David L. , York Brian , Feng Qin , McKenna Neil J. , Dasgupta Subhamoy , Lonard David M. , O’Malley Bert W.
Published: February 2021

A subset of CD4 + lymphocytes, regulatory T cells (Tregs), are necessary for central tolerance and function as suppressors of autoimmunity against self-antigens. The SRC-3 coactivator is an oncogene in multiple cancers and is capable of potentiating numerous transcription factors in a wide variety of cell types. Src-3 knockout mice display broad lymphoproliferation and hypersensitivity to systemic inflammation. Using publicly available bioinformatics data and directed cellular approaches, we show that SRC-3 also is highly enriched in Tregs in mice and humans. Human Tregs lose phenotypic characteristics when SRC-3 is depleted or pharmacologically inhibited, including failure of induction from resting T cells and loss of the ability to suppress proliferation of stimulated T cells. These data support a model for SRC-3 as a coactivator that actively participates in protection from autoimmunity and may support immune evasion of cancers by contributing to the biology of Tregs.
Machine intelligence identifies soluble TNFa as a therapeutic target for spinal cord injury
Authors: Huie J. R. , Ferguson A. R. , Kyritsis N. , Pan J. Z. , Irvine K.-A. , Nielson J. L. , Schupp P. G. , Oldham M. C. , Gensel J. C. , Lin A. , Segal M. R. , Ratan R. R. , Bresnahan J. C. , Beattie M. S.
Published: February 2021

Traumatic spinal cord injury (SCI) produces a complex syndrome that is expressed across multiple endpoints ranging from molecular and cellular changes to functional behavioral deficits. Effective therapeutic strategies for CNS injury are therefore likely to manifest multi-factorial effects across a broad range of biological and functional outcome measures. Thus, multivariate analytic approaches are needed to capture the linkage between biological and neurobehavioral outcomes. Injury-induced neuroinflammation (NI) presents a particularly challenging therapeutic target, since NI is involved in both degeneration and repair. Here, we used big-data integration and large-scale analytics to examine a large dataset of preclinical efficacy tests combining five different blinded, fully counter-balanced treatment trials for different acute anti-inflammatory treatments for cervical spinal cord injury in rats. Multi-dimensional discovery, using topological data analysis (TDA) and principal components analysis (PCA) revealed that only one showed consistent multidimensional syndromic benefit: intrathecal application of recombinant soluble TNFα receptor 1 (sTNFR1), which showed an inverse-U dose response efficacy. Using the optimal acute dose, we showed that clinically-relevant 90 min delayed treatment profoundly affected multiple biological indices of NI in the first 48 h after injury, including reduction in pro-inflammatory cytokines and gene expression of a coherent complex of acute inflammatory mediators and receptors. Further, a 90 min delayed bolus dose of sTNFR1 reduced the expression of NI markers in the chronic perilesional spinal cord, and consistently improved neurological function over 6 weeks post SCI. These results provide validation of a novel strategy for precision preclinical drug discovery that is likely to improve translation in the difficult landscape of CNS trauma, and confirm the importance of TNFα signaling as a therapeutic target.
Comparative genomics of a novel clade shed light on the evolution of the genus Erysipelothrix and characterise an emerging species
Authors: Grazziotin Ana Laura , Vidal Newton M. , Hoepers Patricia Giovana , Reis Thais F. M. , Mesa Dany , Caron Luiz Felipe , Ingberman Max , Beirão Breno C. B. , Zuffo João Paulo , Fonseca Belchiolina Beatriz
Published: February 2021

Erysipelothrix sp. isolates obtained from a deadly outbreak in farmed turkeys were sequenced and compared to representatives of the genus. Phylogenetic trees—supported by digital DNA:DNA hybridization and Average Nucleotide Identity—revealed a novel monophyletic clade comprising isolates from pigs, turkeys, and fish, including isolates previously described as E. sp. Strain 2. Genes coding for the SpaC protein, typically found in E. sp. Strain 2, were detected in all isolates of the clade. Therefore, we confirm E. sp. Strain 2 represents a unique species, that despite its official name “Erysipelothrix piscisicarius” (meaning a killer of fish), may be isolated from a broad host range. Core genome analysis showed that the pathogenic species of this genus, E. rhusiopathiae and the clade E. sp. Strain 2, are enriched in core functionalities related to nutrient uptake and transport, but not necessarily homologous pathways. For instance, whereas the aerobic DctA transporter may uptake C4-dicarboxylates in both species, the anaerobic DcuC transporter is exclusive of the E. sp. Strain 2. Remarkably, the pan-genome analysis uncovered that genes related to transport and metabolism, recombination and repair, translation and transcription in the fish isolate, within the novel clade, have undergone a genomic reduction through pseudogenization. This reflects distinct selective pressures shaping the genome of species and strains within the genus Erysipelothrix while adapting to their respective niches.
Comparison between optical and digital blur using near visual acuity
Authors: Kordek David , Young Laura K. , Kremláček Jan
Published: February 2021

In a low-cost laboratory setup, we compared visual acuity (VA) for stimuli rendered with Zernike aberrations to an equivalent optical dioptric defocus in emmetropic individuals using a relatively short observing distance of 60 cm. The equivalent spherical refractive error of + 1, + 2 or + 4 D, was applied in the rendering of Landolt Rings. Separately, the refractive error was introduced dioptrically in: (1) unchanged Landolt Rings with an added external lens (+ 1, + 2 or + 4 D) at the subject's eye; (2) same as (1) but with an added accommodation and a vertex distance adjustment. To compare all three approaches, we examined VA in 10 healthy men. Stimuli were observed on a PC CRT screen. For all three levels of refractive error, the pairwise comparison did not show a statistically significant difference between digital blur and accommodation-plus-vertex-distance-adjusted dioptric blur (p < 0.204). The best agreement, determined by Bland–Altman analysis, was measured for + 4 D and was in line with test–retest limits for examination in the clinical population. Our results show that even for a near observing distance, it is possible to use digitally rendered defocus to replicate dioptric blur without a significant change in VA in emmetropic subjects.
Histone deacetylase inhibitors suppress ACE2 and ABO simultaneously, suggesting a preventive potential against COVID-19
Authors: Takahashi Yoichiro , Hayakawa Akira , Sano Rie , Fukuda Haruki , Harada Megumi , Kubo Rieko , Okawa Takafumi , Kominato Yoshihiko
Published: February 2021

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide as a pandemic throughout 2020. Since the virus uses angiotensin-converting enzyme 2 (ACE2) as a receptor for cellular entry, increment of ACE2 would lead to an increased risk of SARS-CoV-2 infection. At the same time, an association of the ABO blood group system with COVID-19 has also been highlighted: there is increasing evidence to suggest that non-O individuals are at higher risk of severe COVID-19 than O individuals. These findings imply that simultaneous suppression of ACE2 and ABO would be a promising approach for prevention or treatment of COVID-19. Notably, we have previously clarified that histone deacetylase inhibitors (HDACIs) are able to suppress ABO expression in vitro. Against this background, we further evaluated the effect of HDACIs on cultured epithelial cell lines, and found that HDACIs suppress both ACE2 and ABO expression simultaneously. Furthermore, the amount of ACE2 protein was shown to be decreased by one of the clinically-used HDACIs, panobinostat, which has been reported to reduce B-antigens on cell surfaces. On the basis of these findings, we conclude that panobinostat could have the potential to serve as a preventive drug against COVID-19.
Construction and validation a nomogram to predict overall survival for colorectal signet ring cell carcinoma
Authors: Diao Jian-dong , Ma Li-xia , Wu Chun-jiao , Liu Xian-hong , Su Xiao-yun , Bi Hong-yu , Bao Bo , Yan Hao-wei , Shi Lei , Yang Yong-jing
Published: February 2021

To construct and validate a nomogram to predict the overall survival (OS) of colorectal signet ring cell carcinoma (SRCC). The potentially eligible cases were obtained against the SEER database from 2004 to 2015. Log-rank test and Cox analysis were conducted to identify the independent prognostic factors for predicting OS. The identified prognostic factors were later integrated for the construction of an OS prediction nomogram. Altogether 2904 eligible cases were identified, and the median survival time was 18 (range: 0–155) months. As suggested by multivariate analysis, age, primary site, grade, tumor size, T stage, N stage, M stage, surgery, lymph node dissection and chemotherapy were identified as the independent factors for predicting OS. Afterwards, the above variables were incorporated into the nomogram. The C-index indicated better discriminatory ability of the nomogram than AJCC 8th TNM staging and SEER summary stage systems (both P < 0.001). Calibration plots further showed good consistency between the nomogram prediction and actual observation. The time independent area under the curves (tAUCs) for 3-year and 5-year OS in nomogram were larger than AJCC and SEER summary stage system. The constructed nomogram could potentially predict the survival of colorectal SRCC individuals.
Considering serum alanine aminotransferase and gamma-glutamyltransferase levels together strengthen the prediction of impaired fasting glucose risk: a cross-sectional and longitudinal study
Authors: Jeong Ji Hye , Jung Susie , Kim Kyu-Nam
Published: February 2021

Emerging data suggest that an increase in serum alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) as biomarkers of oxidative stress are associated with increased risk of impaired fasting glucose (IFG). The present study was an investigation of whether an increase in serum ALT and GGT had a combined effect on increasing IFG risk through cross-sectional and longitudinal studies. In the cross-sectional study, data were analyzed from 9937 subjects without diabetes who underwent health check-ups between 1999 and 2001 (baseline data). In the longitudinal study, 6390 subjects were analyzed who had been rechecked between 2009 and 2014, excluding IFG patients from baseline data. In cross-sectional analysis, adjusted odds ratio (OR) of IFG in the fourth quartile of both ALT and GGT was 1.829 (95% confidence interval [CI] 1.545–2.164) compared with the reference group (1st and 2nd quartiles of ALT and GGT). In longitudinal analysis, IFG probability increased gradually with an increase in the circulating levels of ALT and GGT. Adjusted hazard ratios for developing IFG in the fourth quartile of both ALT and GGT was 1.625 (95% CI 1.263–2.091) compared with the reference group (1st and 2nd quartiles). Increased serum ALT and GGT levels are well associated with IFG after potential confounders are adjusted for, and elevated ALT and GGT at the same time can have a combined effect in predicting the development of IFG.
Pangenome analysis reveals genetic isolation in Campylobacter hyointestinalis subspecies adapted to different mammalian hosts
Authors: Costa Daniela , Lévesque Simon , Kumar Nitin , Fresia Pablo , Ferrés Ignacio , Lawley Trevor D. , Iraola Gregorio
Published: February 2021

Campylobacter hyointestinalis is an emerging pathogen currently divided in two subspecies: C. hyointestinalis subsp. lawsonii which is predominantly recovered from pigs, and C. hyointestinalis subsp. hyointestinalis which can be found in a much wider range of mammalian hosts. Despite C. hyointestinalis being reported as an emerging pathogen, its evolutionary and host-associated diversification patterns are still vastly unexplored. For this reason, we generated whole-genome sequences of 13 C. hyointestinalis subsp. hyointestinalis strains and performed a comprehensive comparative analysis including publicly available C. hyointestinalis subsp. hyointestinalis and C. hyointestinalis subsp. lawsonii genomes, to gain insight into the genomic variation of these differentially-adapted subspecies. Both subspecies are distinct phylogenetic lineages which present an apparent barrier to homologous recombination, suggesting genetic isolation. This is further supported by accessory gene patterns that recapitulate the core genome phylogeny. Additionally, C. hyointestinalis subsp. hyointestinalis presents a bigger and more diverse accessory genome, which probably reflects its capacity to colonize different mammalian hosts unlike C. hyointestinalis subsp. lawsonii that is presumably host-restricted. This greater plasticity in the accessory genome of C. hyointestinalis subsp. hyointestinalis correlates to a higher incidence of genome-wide recombination events, that may be the underlying mechanism driving its diversification. Concordantly, both subspecies present distinct patterns of gene families involved in genome plasticity and DNA repair like CRISPR-associated proteins and restriction-modification systems. Together, our results provide an overview of the genetic mechanisms shaping the genomes of C. hyointestinalis subspecies, contributing to understand the biology of Campylobacter species that are increasingly recognized as emerging pathogens.
Author Correction: A causal role for the right angular gyrus in self-location mediated perspective taking
Authors: de Boer D. M. L. , Johnston P. J. , Kerr G. , Meinzer M. , Cleeremans A.
Published: February 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Involvement of bilateral insula in brand extension evaluation: an fMRI study
Authors: Yang Taeyang , Kim Ji-Hyun , Kim Junsuk , Kim Sung-Phil
Published: February 2021

The present study aims to investigate functional involvement of brain areas in consumers’ evaluation of brand extension that refers to the use of well-established brand for launching new offerings. During functional magnetic resonance imaging (fMRI) scanning, participants viewed a beverage brand name followed by an extension goods name selected from the beverage or household appliance categories. They responded acceptability to given brand extension. Both acceptability responses and reaction time revealed a noticeable pattern that participants responded to acceptable stimuli more carefully. General linear model (GLM) analyses revealed the involvement of insular activity in brand extension evaluation. Especially, insular activity was lateralized according to valence. Furthermore, its activity could explain behavioral response in parametric modulation model. According to these results, we speculate that insula activity is relevant to emotional processing. Finally, we divided neural activities during brand extension into separated clusters using a hierarchical clustering-based connectivity analysis. Excluding two of them related to sensorimotor functions for behavioral responses, the remaining cluster, including bilateral insula, was likely to reflect brand extension assessment. Hence, we speculate that consumers’ brand extension evaluation may involve emotional processes, shown as insular activity.
Distinct temporal features of genuine and deliberate facial expressions of surprise
Authors: Namba Shushi , Matsui Hiroshi , Zloteanu Mircea
Published: February 2021

The physical properties of genuine and deliberate facial expressions remain elusive. This study focuses on observable dynamic differences between genuine and deliberate expressions of surprise based on the temporal structure of facial parts during emotional expression. Facial expressions of surprise were elicited using multiple methods and video recorded: senders were filmed as they experienced genuine surprise in response to a jack-in-the-box (Genuine), other senders were asked to produce deliberate surprise with no preparation (Improvised), by mimicking the expression of another (External), or by reproducing the surprised face after having first experienced genuine surprise (Rehearsed). A total of 127 videos were analyzed, and moment-to-moment movements of eyelids and eyebrows were annotated with deep learning-based tracking software. Results showed that all surprise displays were mainly composed of raising eyebrows and eyelids movements. Genuine displays included horizontal movement in the left part of the face, but also showed the weakest movement coupling of all conditions. External displays had faster eyebrow and eyelid movement, while Improvised displays showed the strongest coupling of movements. The findings demonstrate the importance of dynamic information in the encoding of genuine and deliberate expressions of surprise and the importance of the production method employed in research.
Expansion and characterization of bone marrow derived human mesenchymal stromal cells in serum-free conditions
Authors: Bhat Samatha , Viswanathan Pachaiyappan , Chandanala Shashank , Prasanna S. Jyothi , Seetharam Raviraja N.
Published: February 2021

Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are gaining increasing importance in the field of regenerative medicine. Although therapeutic value of MSCs is now being established through many clinical trials, issues have been raised regarding their expansion as per regulatory guidelines. Fetal bovine serum usage in cell therapy poses difficulties due to its less-defined, highly variable composition and safety issues. Hence, there is a need for transition from serum-based to serum-free media (SFM). Since SFM are cell type-specific, a precise analysis of the properties of MSCs cultured in SFM is required to determine the most suitable one. Six different commercially available low serum/SFM with two different seeding densities were evaluated to explore their ability to support the growth and expansion of BM-MSCs and assess the characteristics of BM-MSCs cultured in these media. Except for one of the SFM, all other media tested supported the growth of BM-MSCs at a low seeding density. No significant differences were observed in the expression of MSC specific markers among the various media tested. In contrary, the population doubling time, cell yield, potency, colony-forming ability, differentiation potential, and immunosuppressive properties of MSCs varied with one another. We show that SFM tested supports the growth and expansion of BM-MSCs even at low seeding density and may serve as possible replacement for animal-derived serum.
Polyglycolic acid sheet covering to prevent recurrence after surgery for spontaneous pneumothorax: a meta-analysis
Authors: Kadomatsu Yuka , Fukui Takayuki , Mori Shoichi , Chen-Yoshikawa Toyofumi Fengshi , Wakai Kenji
Published: February 2021

The coverage technique using absorbable mesh was first described in a European guideline published in 2015 as a preventive method for the recurrence of spontaneous pneumothorax. We performed a meta-analysis based on a literature search of primary studies that compared the postoperative recurrence rate of primary spontaneous pneumothorax between the use and nonuse of polyglycolic acid sheet coverage. Two reviewers independently selected and evaluated the quality of the relevant studies. The risk ratio in each study was calculated in a random-effect meta-analysis. Statistical heterogeneity among the included studies was quantitatively evaluated using the I2 index, and publication bias was assessed using a funnel plot. A total of 19 retrospective cohort studies were analyzed: 1524 patients who underwent wedge resection alone (the control group) and 1579 who received additional sheet coverage. Polyglycolic acid sheet coverage was associated with a lower recurrence rate than that in the control group (risk ratio: 0.27, 95% confidence interval 0.20–0.37, P < 0.001; I2 0%). The funnel plot suggested possible publication bias. The covering technique reduced the recurrence rate of pneumothorax after thoracoscopic surgery to one-fourth.
Physician requirements for adoption of telehealth following the SARS-CoV-2 pandemic
Authors: Hodgkins Michael , Barron Meg , Jevaji Shireesha , Lloyd Stacy
Published: February 2021

It took the advent of SARS-CoV-2, a “black swan event”, to widely introduce telehealth, remote care, and virtual house calls. Prior to the epidemic (2019), the American Medical Association (AMA) conducted a routine study to compare physicians’ adoption of emerging technologies to a similar survey in 2016. Most notable was a doubling in the adoption of telehealth/virtual technology to 28% and increases in the use of remote monitoring and management for improved care (13–22%). These results may now seem insignificant when compared to the unprecedented surge in telehealth visits because of SARS-CoV-2. Even as this surge levels off and begins to decline, many observers believe we will continue to see a persistent increase in the use of virtual visits compared to face-to-face care. The requirements for adoption communicated by physicians in both the 2016 and 2019 surveys are now more relevant than ever: Is remote care as effective as in-person care and how best to determine when to use these modalities? How do I safeguard my patients and my practice from liability and privacy concerns? How do I optimize using these technologies in my practice and, especially integration with my EHR and workflows to improve efficiency? And how will a mix of virtual and in-person visits affect practice revenue and sustainability? Consumers have also expressed concerns about payment for virtual visits as well as privacy and quality of care. If telehealth and remote care are here to stay, continuing to track their impact during the current public health emergency is critically important to address so that policymakers and insurers will take necessary steps to ensure that the “new normal” will reflect a health care delivery model that can provide comparable or improved results today and into the future.