bluuebunny/crossref_metadata_2025 huggingface dataset:
Network extraction by routing optimization
Authors: Baptista Diego , Leite Daniela , Facca Enrico , Putti Mario , De Bacco Caterina
Published: November 2020

Routing optimization is a relevant problem in many contexts. Solving directly this type of optimization problem is often computationally intractable. Recent studies suggest that one can instead turn this problem into one of solving a dynamical system of equations, which can instead be solved efficiently using numerical methods. This results in enabling the acquisition of optimal network topologies from a variety of routing problems. However, the actual extraction of the solution in terms of a final network topology relies on numerical details which can prevent an accurate investigation of their topological properties. In fact, in this context, theoretical results are fully accessible only to an expert audience and ready-to-use implementations for non-experts are rarely available or insufficiently documented. In particular, in this framework, final graph acquisition is a challenging problem in-and-of-itself. Here we introduce a method to extract network topologies from dynamical equations related to routing optimization under various parameters’ settings. Our method is made of three steps: first, it extracts an optimal trajectory by solving a dynamical system, then it pre-extracts a network, and finally, it filters out potential redundancies. Remarkably, we propose a principled model to address the filtering in the last step, and give a quantitative interpretation in terms of a transport-related cost function. This principled filtering can be applied to more general problems such as network extraction from images, thus going beyond the scenarios envisioned in the first step. Overall, this novel algorithm allows practitioners to easily extract optimal network topologies by combining basic tools from numerical methods, optimization and network theory. Thus, we provide an alternative to manual graph extraction which allows a grounded extraction from a large variety of optimal topologies. The analysis of these may open up the possibility to gain new insights into the structure and function of optimal networks. We provide an open source implementation of the code online.
Multiscale simulation of the focused electron beam induced deposition process
Authors: de Vera Pablo , Azzolini Martina , Sushko Gennady , Abril Isabel , Garcia-Molina Rafael , Dapor Maurizio , Solov’yov Ilia A. , Solov’yov Andrey V.
Published: November 2020

Focused electron beam induced deposition (FEBID) is a powerful technique for 3D-printing of complex nanodevices. However, for resolutions below 10 nm, it struggles to control size, morphology and composition of the structures, due to a lack of molecular-level understanding of the underlying irradiation-driven chemistry (IDC). Computational modeling is a tool to comprehend and further optimize FEBID-related technologies. Here we utilize a novel multiscale methodology which couples Monte Carlo simulations for radiation transport with irradiation-driven molecular dynamics for simulating IDC with atomistic resolution. Through an in depth analysis of $$\hbox {W(CO)}_6$$

W(CO)
6

deposition on $$\hbox {SiO}_2$$

SiO
2

and its subsequent irradiation with electrons, we provide a comprehensive description of the FEBID process and its intrinsic operation. Our analysis reveals that simulations deliver unprecedented results in modeling the FEBID process, demonstrating an excellent agreement with available experimental data of the simulated nanomaterial composition, microstructure and growth rate as a function of the primary beam parameters. The generality of the methodology provides a powerful tool to study versatile problems where IDC and multiscale phenomena play an essential role.
Topical delivery of a small molecule RUNX1 transcription factor inhibitor for the treatment of proliferative vitreoretinopathy
Authors: Delgado-Tirado Santiago , Amarnani Dhanesh , Zhao Guannan , Rossin Elizabeth J. , Eliott Dean , Miller John B. , Greene Whitney A. , Ramos Leslie , Arevalo-Alquichire Said , Leyton-Cifuentes David , Gonzalez-Buendia Lucia , Isaacs-Bernal Daniela , Whitmore Hannah A. B. , Chmielewska Natalia , Duffy Brandon V. , Kim Eric , Wang Heuy-Ching , Ruiz-Moreno Jose M. , Kim Leo A. , Arboleda-Velasquez Joseph F.
Published: November 2020

Proliferative vitreoretinopathy (PVR) is the leading cause of retinal detachment surgery failure. Despite significant advances in vitreoretinal surgery, it still remains without an effective prophylactic or therapeutic medical treatment. After ocular injury or retinal detachment, misplaced retinal cells undergo epithelial to mesenchymal transition (EMT) to form contractile membranes within the eye. We identified Runt-related transcription factor 1 (RUNX1) as a gene highly expressed in surgically-removed human PVR specimens. RUNX1 upregulation was a hallmark of EMT in primary cultures derived from human PVR membranes (C-PVR). The inhibition of RUNX1 reduced proliferation of human C-PVR cells in vitro, and curbed growth of freshly isolated human PVR membranes in an explant assay. We formulated Ro5-3335, a lipophilic small molecule RUNX1 inhibitor, into a nanoemulsion that when administered topically curbed the progression of disease in a novel rabbit model of mild PVR developed using C-PVR cells. Mass spectrometry analysis detected 2.67 ng/mL of Ro5-3335 within the vitreous cavity after treatment. This work shows a critical role for RUNX1 in PVR and supports the feasibility of targeting RUNX1 within the eye for the treatment of an EMT-mediated condition using a topical ophthalmic agent.
Author Correction: NOVA1 induction by inflammation and NOVA1 suppression by epigenetic regulation in head and neck squamous cell carcinoma
Authors: Kim Eun Kyung , Cho Yoon Ah , Seo Mi-kyoung , Ryu Hyunmi , Cho Byoung Chul , Koh Yoon Woo , Yoon Sun Och
Published: November 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
IL-10 based immunomodulation initiated at birth extends lifespan in a familial mouse model of amyotrophic lateral sclerosis
Authors: Strickland Michael R. , Ibanez Kristen R. , Yaroshenko Mariya , Diaz Carolina Ceballos , Borchelt David R. , Chakrabarty Paramita
Published: November 2020

Inflammatory signaling is thought to modulate the neurodegenerative cascade in amyotrophic lateral sclerosis (ALS). We have previously shown that expression of Interleukin-10 (IL-10), a classical anti-inflammatory cytokine, extends lifespan in the SOD1-G93A mouse model of familial ALS. Here we test whether co-expression of the decoy chemokine receptor M3, that can scavenge inflammatory chemokines, augments the efficacy of IL-10. We found that recombinant adeno-associated virus (AAV)-mediated expression of IL-10, alone, or in combination with M3, resulted in modest extension of lifespan relative to control SOD1-G93A cohort. Interestingly neither AAV-M3 alone nor AAV-IL-10 + AAV-M3 extend survival beyond that of the AAV-IL-10 alone cohort. Focused transcriptomic analysis revealed induction of innate immunity and phagocytotic pathways in presymptomatic SOD1-G93A mice expressing IL-10 + M3 or IL-10 alone. Further, while IL-10 expression increased microglial burden, the IL-10 + M3 group showed lower microglial burden, suggesting that M3 can successfully lower microgliosis before disease onset. Our data demonstrates that over-expression of an anti-inflammatory cytokine and a decoy chemokine receptor can modulate inflammatory processes in SOD1-G93A mice, modestly delaying the age to paralysis. This suggests that multiple inflammatory pathways can be targeted simultaneously in neurodegenerative disease and supports consideration of adapting these approaches to treatment of ALS and related disorders.
Investigation of COVID-19 comorbidities reveals genes and pathways coincident with the SARS-CoV-2 viral disease
Authors: Dolan Mary E. , Hill David P. , Mukherjee Gaurab , McAndrews Monica S. , Chesler Elissa J. , Blake Judith A.
Published: November 2020

The emergence of the SARS-CoV-2 virus and subsequent COVID-19 pandemic initiated intense research into the mechanisms of action for this virus. It was quickly noted that COVID-19 presents more seriously in conjunction with other human disease conditions such as hypertension, diabetes, and lung diseases. We conducted a bioinformatics analysis of COVID-19 comorbidity-associated gene sets, identifying genes and pathways shared among the comorbidities, and evaluated current knowledge about these genes and pathways as related to current information about SARS-CoV-2 infection. We performed our analysis using GeneWeaver (GW), Reactome, and several biomedical ontologies to represent and compare common COVID-19 comorbidities. Phenotypic analysis of shared genes revealed significant enrichment for immune system phenotypes and for cardiovascular-related phenotypes, which might point to alleles and phenotypes in mouse models that could be evaluated for clues to COVID-19 severity. Through pathway analysis, we identified enriched pathways shared by comorbidity datasets and datasets associated with SARS-CoV-2 infection.
Targeting the endothelin axis as a therapeutic strategy for oral cancer metastasis and pain
Authors: Dang Dongmin , Ye Yi , Aouizerat Bradley E. , Patel Yogin K. , Viet Dan T. , Chan King Chong , Ono Kentaro , Doan Coleen , Figueroa Johnny D. , Yu Gary , Viet Chi T.
Published: November 2020

Metastasis reduces survival in oral cancer patients and pain is their greatest complaint. We have shown previously that oral cancer metastasis and pain are controlled by the endothelin axis, which is a pathway comprised of the endothelin A and B receptors (ETAR and ETBR). In this study we focus on individual genes of the pathway, demonstrating that the endothelin axis genes are methylated and dysregulated in cancer tissue. Based on these findings in patients, we hypothesize that ETAR and ETBR play dichotomous roles in oral carcinogenesis and pain, such that ETAR activation and silenced ETBR expression result in increased carcinogenesis and pain. We test a treatment strategy that targets the dichotomous functions of the two receptors by inhibiting ETAR with macitentan, an ETAR antagonist approved for treatment of pulmonary hypertension, and re-expressing the ETBR gene with adenovirus transduction, and determine the treatment effect on cancer invasion (i.e., metastasis), proliferation and pain in vitro and in vivo. We demonstrate that combination treatment of macitentan and ETBR gene therapy inhibits invasion, but not proliferation, in cell culture and in a mouse model of tongue cancer. Furthermore, the treatment combination produces an antinociceptive effect through inhibition of endothelin-1 mediated neuronal activation, revealing the analgesic potential of macitentan. Our treatment approach targets a pathway shown to be dysregulated in oral cancer patients, using gene therapy and repurposing an available drug to effectively treat both oral cancer metastasis and pain in a preclinical model.
TERT promoter alterations could provide a solution for Peto’s paradox in rodents
Authors: Vedelek Balázs , Maddali Asha Kiran , Davenova Nurgul , Vedelek Viktor , Boros Imre M.
Published: November 2020

Cancer is a genetic disease caused by changes in gene expression resulting from somatic mutations and epigenetic changes. Although the probability of mutations is proportional with cell number and replication cycles, large bodied species do not develop cancer more frequently than smaller ones. This notion is known as Peto’s paradox, and assumes stronger tumor suppression in larger animals. One of the possible tumor suppressor mechanisms involved could be replicative senescence caused by telomere shortening in the absence of telomerase activity. We analysed telomerase promoter activity and transcription factor binding in mammals to identify the key element of telomerase gene inactivation. We found that the GABPA transcription factor plays a key role in TERT regulation in somatic cells of small rodents, but its binding site is absent in larger beavers. Protein binding and reporter gene assays verify different use of this site in different species. The presence or absence of the GABPA TF site in TERT promoters of rodents correlates with TERT promoter activity; thus it could determine whether replicative senescence plays a tumor suppressor role in these species, which could be in direct relation with body mass. The GABPA TF binding sites that contribute to TERT activity in somatic cells of rodents are analogous to those mutated in human tumors, which activate telomerase by a non-ALT mechanism.
Genome-wide association analysis of the strength of the MAMP-elicited defense response and resistance to target leaf spot in sorghum
Authors: Samira Rozalynne , Kimball Jennifer A. , Samayoa Luis Fernando , Holland James B. , Jamann Tiffany M. , Brown Patrick J. , Stacey Gary , Balint-Kurti Peter J.
Published: November 2020

Plants have the capacity to respond to conserved molecular features known as microbe-associated molecular patterns (MAMPs). The goal of this work was to assess variation in the MAMP response in sorghum, to map loci associated with this variation, and to investigate possible connections with variation in quantitative disease resistance. Using an assay that measures the production of reactive oxygen species, we assessed variation in the MAMP response in a sorghum association mapping population known as the sorghum conversion population (SCP). We identified consistent variation for the response to chitin and flg22—an epitope of flagellin. We identified two SNP loci associated with variation in the flg22 response and one with the chitin response. We also assessed resistance to Target Leaf Spot (TLS) disease caused by the necrotrophic fungus Bipolaris cookei in the SCP. We identified one strong association on chromosome 5 near a previously characterized disease resistance gene. A moderately significant correlation was observed between stronger flg22 response and lower TLS resistance. Possible reasons for this are discussed.
Understanding the lost functionality of ethanol in non-alcoholic beer using sensory evaluation, aroma release and molecular hydrodynamics
Authors: Ramsey Imogen , Dinu Vlad , Linforth Rob , Yakubov Gleb E. , Harding Stephen E. , Yang Qian , Ford Rebecca , Fisk Ian
Published: November 2020

Consumer sensory evaluation, aroma release analysis and biophysical protein analysis were used to investigate the effect of ethanol on the release and perception of flavour in beer (lager and stout) at different ethanol levels (0 and 5% ABV). Consumer study results showed no significant differences in orthonasal perception, yet retronasal results showed that 0% lager was perceived as maltier with reduced fruitiness, sweetness, fullness/body and alcohol warming sensation (p < 0.05). Whilst ethanol alone decreases the aroma release regardless of LogP, the presence of α-amylase selectively reduces the headspace concentration of hydrophobic compounds. It was found that ethanol has a subtle inhibitory effect on the binding of hydrophobic compounds to α-amylase, thereby increasing their headspace concentration in the 5% ABV as compared to the 0% beers. This synergistic ethanol * saliva effect is attributed to the changes in the conformation of α-amylase due to ethanol-induced denaturation. It is hypothesised that the partially unfolded protein structures have a lower number of hydrophobic pockets, leading to a lower capacity to entrap hydrophobic aroma compounds. This supports the hypothesis that ethanol * saliva interactions directly impact the sensory and flavour properties of beer, which would provide a basis for further investigations in reformulation of 0% ABV drinks.
Identification of distinct immune activation profiles in adult humans
Authors: Cezar Renaud , Winter Audrey , Desigaud Delphine , Pastore Manuela , Kundura Lucy , Dupuy Anne-Marie , Cognot Chantal , Vincent Thierry , Reynes Christelle , Dunyach-Remy Catherine , Lavigne Jean-Philippe , Sabatier Robert , Le Merre Patricia , Maggia Elisabeth , Corbeau Pierre
Published: November 2020

Latent infectious agents, microbial translocation, some metabolites and immune cell subpopulations, as well as senescence modulate the level and quality of activation of our immune system. Here, we tested whether various in vivo immune activation profiles may be distinguished in a general population. We measured 43 markers of immune activation by 8-color flow cytometry and ELISA in 150 adults, and performed a double hierarchical clustering of biomarkers and volunteers. We identified five different immune activation profiles. Profile 1 had a high proportion of naïve T cells. By contrast, Profiles 2 and 3 had an elevated percentage of terminally differentiated and of senescent CD4+ T cells and CD8+ T cells, respectively. The fourth profile was characterized by NK cell activation, and the last profile, Profile 5, by a high proportion of monocytes. In search for etiologic factors that could determine these profiles, we observed a high frequency of naïve Treg cells in Profile 1, contrasting with a tendency to a low percentage of Treg cells in Profiles 2 and 3. Moreover, Profile 5 tended to have a high level of 16s ribosomal DNA, a direct marker of microbial translocation. These data are compatible with a model in which specific causes, as the frequency of Treg or the level of microbial translocation, shape specific profiles of immune activation. It will be of interest to analyze whether some of these profiles drive preferentially some morbidities known to be fueled by immune activation, as insulin resistance, atherothrombosis or liver steatosis.
Dichotic listening performance and interhemispheric integration after stress exposure
Authors: Berretz Gesa , Packheiser Julian , Wolf Oliver T. , Ocklenburg Sebastian
Published: November 2020

Functional hemispheric asymmetries (FHAs) have been thought to be relatively stable over time. However, past research has shown that FHAs are more plastic than initially thought. Endocrinological processes have been demonstrated to alter FHAs. As the product of the stress-activated hypothalamus–pituitary–adrenal axis, cortisol influences information processing at every level from stimulus perception to decision making and action. To investigate the influence of acute stress on FHAs, 60 participants performed a Banich–Belger task, as well as a verbal and an emotional dichotic listening task in two sessions. One session included a stress induction via the Trier Social Stress Test, the other session included a control procedure. We calculated across-field advantages (AFAs) in the Banich–Belger task and lateralization quotients for reaction times and responses per side in both dichotic listening tasks. There were no significant differences between the stress and control session in the dichotic listening tasks. In contrast, there was evidence for an influence of cortisol and sympathetic activation indicated by salivary alpha amylase changes on AFAs in the Banich–Belger task. This indicates that acute stress and the related increase in cortisol do not influence dichotic listening performance. However, stress does seem to affect interhemispheric integration of information. Future research using EEG, fMRI and pharmacological interventions is needed to further characterize the relation of hemispheric asymmetries and acute stress.
Long-term molecular surveillance provides clues on a cattle origin for Mycobacterium bovis in Portugal
Authors: Reis Ana C. , Tenreiro Rogério , Albuquerque Teresa , Botelho Ana , Cunha Mónica V.
Published: November 2020

Animal tuberculosis (TB), caused by Mycobacterium bovis, is maintained in Portugal in a multi-host system, with cattle, red deer and wild boar, playing a central role. However, the ecological processes driving transmission are not understood. The main aim of this study was thus to contribute to the reconstruction of the spatiotemporal history of animal TB and to refine knowledge on M. bovis population structure in order to inform novel intervention strategies. A collection of 948 M. bovis isolates obtained during long-term surveillance (2002–2016, 15 years) of cattle (n = 384), red deer (n = 303) and wild boar (n = 261), from the main TB hotspot areas, was characterized by spoligotyping and 8 to 12-loci MIRU-VNTR. Spoligotyping identified 64 profiles and MIRU-VNTR distinguished 2 to 36 subtypes within each spoligotype, enabling differentiation of mixed or clonal populations. Common genotypic profiles within and among livestock and wildlife in the same spatiotemporal context highlighted epidemiological links across hosts and regions, as for example the SB0119-M205 genotype shared by cattle in Beja district or SB0121-M34 shared by the three hosts in Castelo Branco and Beja districts. These genomic data, together with metadata, were integrated in a Bayesian inference framework, identifying five ancestral M. bovis populations. The phylogeographic segregation of M. bovis in specific areas of Portugal where the disease persists locally is postulated. Concurrently, robust statistics indicates an association of the most probable ancient population with cattle and Beja, providing a clue on the origin of animal TB epidemics. This relationship was further confirmed through a multinomial probability model that assessed the influence of host species on spatiotemporal clustering. Two significant clusters were identified, one that persisted between 2004 and 2010, in Beja district, with Barrancos county at the centre, overlapping the central TB core area of the Iberian Peninsula, and highlighting a significant higher risk associated to cattle. The second cluster was predominant in the 2012–2016 period, holding the county Rosmaninhal at the centre, in Castelo Branco district, for which wild boar contributed the most in relative risk. These results provide novel quantitative insights beyond empirical perceptions, that may inform adaptive TB control choices in different regions.
An in silico approach to analyze HCV genotype-specific binding-site variation and its effect on drug–protein interaction
Authors: Khalid Ramsha , Anwar Muhammad Faraz , Raees Muhammad Aanish , Naeem Sadaf , Abidi Syed Hani , Ali Syed
Published: November 2020

Genotype variation in viruses can affect the response of antiviral treatment. Several studies have established approaches to determine genotype-specific variations; however, analyses to determine the effect of these variations on drug–protein interactions remain unraveled. We present an in-silico approach to explore genotype-specific variations and their effect on drug–protein interaction. We have used HCV NS3 helicase and fluoroquinolones as a model for drug–protein interaction and have investigated the effect of amino acid variations in HCV NS3 of genotype 1a, 1b, 2b and 3a on NS3-fluoroquinolone interaction. We retrieved 687, 667, 101 and 248 nucleotide sequences of HCV NS3 genotypes 1a, 1b, 2b, and 3a, respectively, and translated these into amino acid sequences and used for genotype variation analysis, and also to construct 3D protein models for 2b and 3a genotypes. For 1a and 1b, crystal structures were used. Drug–protein interactions were determined using molecular docking analyses. Our results revealed that individual genotype-specific HCV NS3 showed substantial sequence heterogeneity that resulted in variations in docking interactions. We believe that our approach can be extrapolated to include other viruses to study the clinical significance of genotype-specific variations in drug–protein interactions.
Robust spatial ventriloquism effect and trial-by-trial aftereffect under memory interference
Authors: Park Hame , Kayser Christoph
Published: November 2020

Our brain adapts to discrepancies in the sensory inputs. One example is provided by the ventriloquism effect, experienced when the sight and sound of an object are displaced. Here the discrepant multisensory stimuli not only result in a biased localization of the sound, but also recalibrate the perception of subsequent unisensory acoustic information in the so-called ventriloquism aftereffect. This aftereffect has been linked to memory-related processes based on its parallels to general sequential effects in perceptual decision making experiments and insights obtained in neuroimaging studies. For example, we have recently implied memory-related medial parietal regions in the trial-by-trial ventriloquism aftereffect. Here, we tested the hypothesis that the trial-by-trial (or immediate) ventriloquism aftereffect is indeed susceptible to manipulations interfering with working memory. Across three experiments we systematically manipulated the temporal delays between stimuli and response for either the ventriloquism or the aftereffect trials, or added a sensory-motor masking trial in between. Our data reveal no significant impact of either of these manipulations on the aftereffect, suggesting that the recalibration reflected by the trial-by-trial ventriloquism aftereffect is surprisingly resilient to manipulations interfering with memory-related processes.
Performance of polychaete assisted sand filters under contrasting nutrient loads in an integrated multi-trophic aquaculture (IMTA) system
Authors: Jerónimo Daniel , Lillebø Ana Isabel , Santos Andreia , Cremades Javier , Calado Ricardo
Published: November 2020

Polychaete assisted sand filters (PASFs) allow to combine a highly efficient retention of particulate organic matter (POM) present in aquaculture effluent water and turn otherwise wasted nutrients into valuable worm biomass, following an integrated multi-trophic aquaculture (IMTA) approach. This study evaluated the bioremediation and biomass production performances of three sets of PASFs stocked with ragworms (Hediste diversicolor) placed in three different locations of an open marine land-based IMTA system. The higher organic matter (OM) recorded in the substrate of the systems which received higher POM content (Raw and Df PASFs – filtered raw and screened by drum filter effluent, respectively) likely prompted a superior reproductive success of stocked polychaetes (final densities 2–7 times higher than initial stock; ≈1000–3000 ind. m−2). Bioremediation efficiencies of ≈70% of supplied POM (≈1.5–1.8 mg L−1) were reported in these systems. The PASFs with lower content of OM in the substrate (Df + Alg PASFs – filtered effluent previously screened by drum filter and macroalgae biofilter) differed significantly from the other two, with stocked polychaetes displaying a poorer reproductive success. The PASFs were naturally colonized with marine invertebrates, with the polychaetes Diopatra neapolitana, Terebella lapidaria and Sabella cf. pavonina being some of the species identified with potential for IMTA.
Microbiota attenuates chicken transmission-exacerbated campylobacteriosis in Il10−/− mice
Authors: Fu Ying , Almansour Ayidh , Bansal Mohit , Alenezi Tahrir , Alrubaye Bilal , Wang Hong , Sun Xiaolun
Published: November 2020

Campylobacter jejuni is a prevalent foodborne pathogen mainly transmitting through poultry. It remains unknown how chicken-transmitted C. jejuni and microbiota impact on human campylobacteriosis. Campylobacter jejuni AR101 (Cj-P0) was introduced to chickens and isolated as passage 1 (Cj-P1). Campylobacter jejuni Cj-P1-DCA-Anaero was isolated from Cj-P0-infected birds transplanted with DCA-modulated anaerobic microbiota. Specific pathogen free Il10−/− mice were gavaged with antibiotic clindamycin and then infected with Cj-P0, Cj-P1, or Cj-P1-DCA-Anaero, respectively. After 8 days post infection, Il10−/− mice infected with Cj-P1 demonstrated severe morbidity and bloody diarrhea and the experiment had to be terminated. Cj-P1 induced more severe histopathology compared to Cj-P0, suggesting that chicken transmission increased C. jejuni virulence. Importantly, mice infected with Cj-P1-DCA-Anaero showed attenuation of intestinal inflammation compared to Cj-P1. At the cellular level, Cj-P1 induced more C. jejuni invasion and neutrophil infiltration into the Il10−/− mouse colon tissue compared to Cj-P0, which was attenuated with Cj-P1-DCA-Anaero. At the molecular level, Cj-P1 induced elevated inflammatory mediator mRNA accumulation of Il17a, Il1β, and Cxcl1 in the colon compared to Cj-P0, while Cj-P1-DCA-Anaero showed reduction of the inflammatory gene expression. In conclusion, our data suggest that DCA-modulated anaerobes attenuate chicken-transmitted campylobacteriosis in mice and it is important to control the elevation of C. jejuni virulence during chicken transmission process.
HIF1α activation in dendritic cells under sterile conditions promotes an anti-inflammatory phenotype through accumulation of intracellular lipids
Authors: Wood Elizabeth G. , Macdougall Claire E. , Blythe Hazel , Clément Marc , Colas Romain A. , Dalli Jesmond , Marelli-Berg Federica , Longhi M. Paula
Published: November 2020

Obesity is among the leading causes of elevated cardiovascular disease mortality and morbidity. Adipose tissue dysfunction, insulin resistance and inflammation are recognized as important risk factors for the development of cardiovascular disorders in obesity. Hypoxia appears to be a key factor in adipose tissue dysfunction affecting not only adipocytes but also immune cell function. Here we examined the effect of hypoxia-induced transcription factor HIF1α activation on classical dendritic cell (cDCs) function during obesity. We found that deletion of Hif1α on cDCs results in enhanced adipose-tissue inflammation and atherosclerotic plaque formation in a mouse model of obesity. This effect is mediated by HIF1α-mediated increased lipid synthesis, accumulation of lipid droplets and alter synthesis of lipid mediators. Our findings demonstrate that HIF1α activation in cDCs is necessary to control vessel wall inflammation.
Conserved interactions required for inhibition of the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Authors: Shitrit Alina , Zaidman Daniel , Kalid Ori , Bloch Itai , Doron Dvir , Yarnizky Tali , Buch Idit , Segev Idan , Ben-Zeev Efrat , Segev Elad , Kobiler Oren
Published: November 2020

The COVID-19 pandemic caused by the SARS-CoV-2 requires a fast development of antiviral drugs. SARS-CoV-2 viral main protease (Mpro, also called 3C‐like protease, 3CLpro) is a potential target for drug design. Crystal and co-crystal structures of the SARS-CoV-2 Mpro have been solved, enabling the rational design of inhibitory compounds. In this study we analyzed the available SARS-CoV-2 and the highly similar SARS-CoV-1 crystal structures. We identified within the active site of the Mpro, in addition to the inhibitory ligands’ interaction with the catalytic C145, two key H-bond interactions with the conserved H163 and E166 residues. Both H-bond interactions are present in almost all co-crystals and are likely to occur also during the viral polypeptide cleavage process as suggested from docking of the Mpro cleavage recognition sequence. We screened in silico a library of 6900 FDA-approved drugs (ChEMBL) and filtered using these key interactions and selected 29 non-covalent compounds predicted to bind to the protease. Additional screen, using DOCKovalent was carried out on DrugBank library (11,414 experimental and approved drugs) and resulted in 6 covalent compounds. The selected compounds from both screens were tested in vitro by a protease activity inhibition assay. Two compounds showed activity at the 50 µM concentration range. Our analysis and findings can facilitate and focus the development of highly potent inhibitors against SARS-CoV-2 infection.
Ingestive behaviors in bearded capuchins (Sapajus libidinosus)
Authors: Laird Myra F. , Wright Barth W. , Rivera Annie O. , Fogaça Mariana Dutra , van Casteren Adam , Fragaszy Dorothy M. , Izar Patricia , Visalberghi Elisabetta , Scott Robert S. , Strait David S. , Ross Callum F. , Wright Kristin A.
Published: November 2020

The biomechanical and adaptive significance of variation in craniodental and mandibular morphology in fossil hominins is not always clear, at least in part because of a poor understanding of how different feeding behaviors impact feeding system design (form–function relationships). While laboratory studies suggest that ingestive behaviors produce variable loading, stress, and strain regimes in the cranium and mandible, understanding the relative importance of these behaviors for feeding system design requires data on their use in wild populations. Here we assess the frequencies and durations of manual, ingestive, and masticatory behaviors from more than 1400 observations of feeding behaviors video-recorded in a wild population of bearded capuchins (Sapajus libidinosus) at Fazenda Boa Vista in Piauí, Brazil. Our results suggest that ingestive behaviors in wildSapajus libidinosuswere used for a range of food material properties and typically performed using the anterior dentition. Coupled with previous laboratory work indicating that ingestive behaviors are associated with higher mandibular strain magnitudes than mastication, these results suggest that ingestive behaviors may play an important role in craniodental and mandibular design in capuchins and may be reflected in robust adaptations in fossil hominins.
Wide-ranging transcriptomic analysis of Poncirus trifoliata, Citrus sunki, Citrus sinensis and contrasting hybrids reveals HLB tolerance mechanisms
Authors: Curtolo Maiara , de Souza Pacheco Inaiara , Boava Leonardo Pires , Takita Marco Aurélio , Granato Laís Moreira , Galdeano Diogo Manzano , de Souza Alessandra Alves , Cristofani-Yaly Mariângela , Machado Marcos Antonio
Published: November 2020

Huanglongbing (HLB), caused mainly by ‘Candidatus Liberibacter asiaticus’ (CLas), is the most devastating citrus disease because all commercial species are susceptible. HLB tolerance has been observed in Poncirus trifoliata and their hybrids. A wide-ranging transcriptomic analysis using contrasting genotypes regarding HLB severity was performed to identify the genetic mechanism associated with tolerance to HLB. The genotypes included Citrus sinensis, Citrus sunki, Poncirus trifoliata and three distinct groups of hybrids obtained from crosses between C. sunki and P. trifoliata. According to bacterial titer and symptomatology studies, the hybrids were clustered as susceptible, tolerant and resistant to HLB. In P. trifoliata and resistant hybrids, genes related to specific pathways were differentially expressed, in contrast to C. sinensis, C. sunki and susceptible hybrids, where several pathways were reprogrammed in response to CLas. Notably, a genetic tolerance mechanism was associated with the downregulation of gibberellin (GA) synthesis and the induction of cell wall strengthening. These defense mechanisms were triggered by a class of receptor-related genes and the induction of WRKY transcription factors. These results led us to build a hypothetical model to understand the genetic mechanisms involved in HLB tolerance that can be used as target guidance to develop citrus varieties or rootstocks with potential resistance to HLB.
Fabrication of hyaline-like cartilage constructs using mesenchymal stem cell sheets
Authors: Thorp Hallie , Kim Kyungsook , Kondo Makoto , Grainger David W. , Okano Teruo
Published: November 2020

Cell and tissue engineering approaches for articular cartilage regeneration increasingly focus on mesenchymal stem cells (MSCs) as allogeneic cell sources, based on availability and innate chondrogenic potential. Many MSCs exhibit chondrogenic potential as three-dimensional (3D) cultures (i.e. pellets and seeded biomaterial scaffolds) in vitro; however, these constructs present engraftment, biocompatibility, and cell functionality limitations in vivo. Cell sheet technology maintains cell functionality as scaffold-free constructs while enabling direct cell transplantation from in vitro culture to targeted sites in vivo. The present study aims to develop transplantable hyaline-like cartilage constructs by stimulating MSC chondrogenic differentiation as cell sheets. To achieve this goal, 3D MSC sheets are prepared, exploiting spontaneous post-detachment cell sheet contraction, and chondrogenically induced. Results support 3D MSC sheets’ chondrogenic differentiation to hyaline cartilage in vitro via post-contraction cytoskeletal reorganization and structural transformations. These 3D cell sheets’ initial thickness and cellular densities may also modulate MSC-derived chondrocyte hypertrophy in vitro. Furthermore, chondrogenically differentiated cell sheets adhere directly to cartilage surfaces via retention of adhesion molecules while maintaining the cell sheets’ characteristics. Together, these data support the utility of cell sheet technology for fabricating scaffold-free, hyaline-like cartilage constructs from MSCs for future transplantable articular cartilage regeneration therapies.
Characteristics of banana B genome MADS-box family demonstrate their roles in fruit development, ripening, and stress
Authors: Zheng Yunke , Liu Mengting , Jia Caihong , Wang Jingyi , Xu Biyu , Jin Zhiqiang , Li Wen , Liu Juhua
Published: November 2020

MADS-box genes are critical regulators of growth and development in flowering plants. Sequencing of the Musa balbisiana (B) genome has provided a platform for the systematic analysis of the MADS-box gene family in the important banana ancestor Musa balbisiana. Seventy-seven MADS-box genes, including 18 type I and 59 type II, were strictly identified from the banana (Pisang Klutuk Wulung, PKW, 2n = 2x = 22) B genome. These genes have been preferentially placed on the banana B genome. Evolutionary analysis suggested that M. balbisiana MCM1-AGAMOUS-DEFICIENS-SRF (MbMADS) might be organized into the MIKCc, MIKC*, Mα, Mβ, and Mγ groups according to the phylogeny. MIKCc was then further categorized into 10 subfamilies according to conserved motif and gene structure analyses. The well-defined MADS-box genes highlight gene birth and death in banana. MbMADSes originated from the same ancestor as MaMADSes. Transcriptome analysis in cultivated banana (ABB) revealed that MbMADSes were conserved and differentially expressed in several organs, in various fruit developing and ripening stages, and in stress treatments, indicating the participation of these genes in fruit development, ripening, and stress responses. Of note, SEP/AGL2 and AG, as well as other several type II MADS-box genes, including the STMADS11 and TM3/SOC1 subfamilies, indicated elevated expression throughout banana fruit development, ripening, and stress treatments, indicating their new parts in controlling fruit development and ripening. According to the co-expression network analysis, MbMADS75 interacted with bZIP and seven other transcription factors to perform its function. This systematic analysis reveals fruit development, ripening, and stress candidate MbMADSes genes for additional functional studies in plants, improving our understanding of the transcriptional regulation of MbMADSes genes and providing a base for genetic modification of MADS-mediated fruit development, ripening, and stress.
Octopus arms exhibit exceptional flexibility
Authors: Kennedy E. B. Lane , Buresch Kendra C. , Boinapally Preethi , Hanlon Roger T.
Published: November 2020

The octopus arm is often referred to as one of the most flexible limbs in nature, yet this assumption requires detailed inspection given that this has not been measured comprehensively for all portions of each arm. We investigated the diversity of arm deformations in Octopus bimaculoides with a frame-by-frame observational analysis of laboratory video footage in which animals were challenged with different tasks. Diverse movements in these hydrostatic arms are produced by some combination of four basic deformations: bending (orally, aborally; inward, outward), torsion (clockwise, counter-clockwise), elongation, and shortening. More than 16,500 arm deformations were observed in 120 min of video. Results showed that all eight arms were capable of all four types of deformation along their lengths and in all directions. Arms function primarily to bring the sucker-lined oral surface in contact with target surfaces. Bending was the most common deformation observed, although the proximal third of the arms performed relatively less bending and more shortening and elongation as compared with other arm regions. These findings demonstrate the exceptional flexibility of the octopus arm and provide a basis for investigating motor control of the entire arm, which may aid the future development of soft robotics.
A cyanobacterial photorespiratory bypass model to enhance photosynthesis by rerouting photorespiratory pathway in C3 plants
Authors: Khurshid Ghazal , Abbassi Anum Zeb , Khalid Muhammad Farhan , Gondal Mahnoor Naseer , Naqvi Tatheer Alam , Shah Mohammad Maroof , Chaudhary Safee Ullah , Ahmad Raza
Published: November 2020

Plants employ photosynthesis to produce sugars for supporting their growth. During photosynthesis, an enzyme Ribulose 1,5 bisphosphate carboxylase/oxygenase (Rubisco) combines its substrate Ribulose 1,5 bisphosphate (RuBP) with CO2 to produce phosphoglycerate (PGA). Alongside, Rubisco also takes up O2 and produce 2-phosphoglycolate (2-PG), a toxic compound broken down into PGA through photorespiration. Photorespiration is not only a resource-demanding process but also results in CO2 loss which affects photosynthetic efficiency in C3 plants. Here, we propose to circumvent photorespiration by adopting the cyanobacterial glycolate decarboxylation pathway into C3 plants. For that, we have integrated the cyanobacterial glycolate decarboxylation pathway into a kinetic model of C3 photosynthetic pathway to evaluate its impact on photosynthesis and photorespiration. Our results show that the cyanobacterial glycolate decarboxylation bypass model exhibits a 10% increase in net photosynthetic rate (A) in comparison with C3 model. Moreover, an increased supply of intercellular CO2 (Ci) from the bypass resulted in a 54.8% increase in PGA while reducing photorespiratory intermediates including glycolate (− 49%) and serine (− 32%). The bypass model, at default conditions, also elucidated a decline in phosphate-based metabolites including RuBP (− 61.3%). The C3 model at elevated level of inorganic phosphate (Pi), exhibited a significant change in RuBP (+ 355%) and PGA (− 98%) which is attributable to the low availability of Ci. Whereas, at elevated Pi, the bypass model exhibited an increase of 73.1% and 33.9% in PGA and RuBP, respectively. Therefore, we deduce a synergistic effect of elevation in CO2 and Pi pool on photosynthesis. We also evaluated the integrative action of CO2, Pi, and Rubisco carboxylation activity (Vcmax) on A and observed that their simultaneous increase raised A by 26%, in the bypass model. Taken together, the study potentiates engineering of cyanobacterial decarboxylation pathway in C3 plants to bypass photorespiration thereby increasing the overall efficiency of photosynthesis.
Elevated temperature, but not decreased pH, impairs reproduction in a temperate fish
Authors: Lopes Ana F. , Faria Ana M. , Dupont Sam
Published: November 2020

Fish reproductive success is linked to the ability of couples to mate and produce clutches that successfully hatch. Environmental stressors like high temperature and low pH can jeopardize this energetically costly process. In this study, exposure to high temperature and low pH was tested on a marine temperate species,Gobiusculus flavescens, to evaluate effects on reproductive performance. Breeding pairs were assigned to different temperatures (+ 0 °C, + 3 °C relative to in situ temperature) and pH levels (8.0, 7.6), in a cross-factorial design for a 3-month period. Reproduction activity, success, and paternal investment were measured throughout the exposure period. Results show reproduction is impaired by elevated temperature, while low pH had little impact. Breeding pairs under high temperature had 3% to 10% hatching success, up to 30% less eggs and eggs up to 20% smaller. Although paternal investment was not affected by tested parameters, males of breeding pairs exposed to elevated temperature had smaller gonadosomatic indexes, which might indicate a lack of investment in the reproductive process. Overall, results show that elevated temperature, expected more frequently in the near future, as a consequence of global warming, may impair key processes like reproduction in temperate fish, with potential consequences for fitness and population replenishment.
Inter-method reliability for determining total and soluble fluorides in child low-fluoride formula dentifrices
Authors: Bijle Mohammed Nadeem , Tsoi James , Ekambaram Manikandan , Lo Edward C. M. , Carey Clifton M. , Yiu Cynthia Kar Yung
Published: November 2020

The study aimed to compare three methods for determining total (TF) and total soluble fluorides (TSF) in 5 child formula dentifrices (CFD) using Inter-method reliability (IMR) statistical approach. The methods were direct acid-hydrolysis (DM), the least-time-consuming method; Modified direct acid-hydrolysis with standard-addition method (MDM), ISO 19448:2018 method; and modified Taves acid-HMDS diffusion analysis (TAD), the claimed gold standard method. A significant difference in the mean difference was observed for all methods at all levels (p < 0.001), except DM and TAD for TF (p = 0.622). A proportional bias was discerned in the agreement distribution between DM and TAD for TF (p < 0.001). The ICC analysis identified significant reliability between all measurements, irrespective of the model, measure, and fluoride type (p < 0.001). For TF and TSF, the IMR between DM and TAD was lower than MDM and TAD for consistency/absolute agreement reliability at single/average measures. The reliability measure for DM and MDM was higher than MDM and TAD for TSF, but was lower than MDM and TAD for TF. The ICC measure for DM-TAD was significantly lower than DM-MDM and MDM-TAD (p < 0.05). The ISO 19448:2018 MDM is a reliable test that can be used as an alternative to TAD/DM for determining TF/TSF in CFD.
Predictors and prognoses of Willisian collateral failure during mechanical thrombectomy
Authors: Lee Seong-Joon , Hwang Yang-Ha , Hong Ji Man , Choi Jin Wook , Kang Dong-Hun , Kim Yong-Won , Kim Yong-Sun , Hong Jeong-Ho , Yoo Joonsang , Kim Chang-Hyun , Ovbiagele Bruce , Demchuk Andrew , Sohn Sung-Il , Lee Jin Soo
Published: November 2020

During mechanical thrombectomy in the anterior cerebral circulation, thrombus embolization resulting in Willisian collateral failure may lead to critical stroke outcomes due to a shutdown of leptomeningeal collaterals. We hypothesized that the outcomes of dynamic Willisian collateral failure (DWF), induced during mechanical thrombectomy, would be associated with grave outcomes. We evaluated this hypothesis in consecutive patients, between January 2011 and May 2016, who underwent mechanical thrombectomy for anterior circulation occlusions, with an onset-to-puncture of 24 h. Patients with initial Willisian collateral failure (IWF) were identified first, with remaining patients classified into the DWF and Willisian collateral sparing (WCS) groups. Comparative and multivariable analyses were performed to predict grave outcomes (3-month modified Rankin Scale score of 5–6). Among 567 patients, 37 were in the IWF group, 38 in the DWF group, and 492 in the WCS group. Compared to the WCS and DWF groups, the IWF group had a higher baseline National Institute of Health Stroke Scale score and lower Alberta Stroke Program Early CT Score. The prevalence of grave outcomes was similarly high in the IWF (48.6%) and DWF (47.4%) groups, but lower in the WCS group (22.0%; p < 0.001). IWF and DWF were independent risk factors for a grave outcome.