bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple introgressions shape mitochondrial evolutionary history inDrosophila paulistorumand theDrosophila willistonigroup
Authors: Baião Guilherme C. , Schneider Daniela I. , Miller Wolfgang J. , Klasson Lisa 
Published: September 2020

ABSTRACTHybridization and the consequent introgression of genomic elements is an important source of genetic diversity for biological lineages. This is particularly evident in young clades in which hybrid incompatibilities are still incomplete and mixing between species is more likely to occur.Drosophila paulistorum, a representative of the NeotropicalDrosophila willistonisubgroup, is a classic model of incipient speciation. The species is divided into six semispecies that show varying degrees of pre- and post-mating incompatibility with each other. In the present study, we investigate the mitochondrial evolutionary history ofD. paulistorumand the willistoni subgroup. For that, we perform phylogenetic and comparative analyses of the complete mitochondrial genomes and draft nuclear assemblies of 25Drosophilalines of the willistoni and saltans species groups. Our results show that the mitochondria ofD. paulistorumare polyphyletic and form two non-sister clades that we name α and β. Identification and analyses of nuclear mitochondrial insertions further reveal that the willistoni subgroup has an α-like mitochondrial ancestor and indicate that both the α and β mitochondria ofD. paulistorumwere acquired through introgression from unknown fly lineages of the willistoni subgroup. We also uncover multiple mitochondrial introgressions acrossD. paulistorumsemispecies and generate novel insight into the evolution of the species.
Deep conservation of ribosome stall sites across RNA processing genes
Authors: Chyżyńska Katarzyna , Labun Kornel , Jones Carl , Grellscheid Sushma N. , Valen Eivind 
Published: September 2020

AbstractThe rate of translation can vary considerably depending on the mRNA template. During the elongation phase the ribosome can transiently pause or permanently stall. A pause can provide the nascent protein with the required time to fold or be transported, while stalling can serve as quality control and trigger degradation of aberrant mRNA and peptide. Ribosome profiling has allowed for the genome-wide detection of such pause and stall sites, but due to library-specific biases, these predictions are often unreliable.Here, we address this by taking advantage of the deep conservation of the protein synthesis machinery, hypothesizing that similar conservation could exist for functionally important positions of ribosome slowdown - here collectively called stall sites. We analyze multiple ribosome profiling datasets from a phylogenetically diverse group of eukaryotes: yeast, fruit fly, zebrafish, mouse, and human and identify conserved stall sites. We find thousands of stall sites across multiple species, with proline, glycine, and negatively charged amino acids being the main facilitators of stalling. Many of the sites are found in RNA processing genes, suggesting that stalling might have a conserved regulatory effect on RNA metabolism. In summary, our results provide a rich resource for the study of conserved stalling and indicate possible roles of stalling in gene regulation.
LncRNA Hmrhl regulates expression of cancer related genes in Chronic Myelogenous Leukemia through chromatin association
Authors: Choudhury Subhendu Roy , Dutta Sangeeta , Bhaduri Utsa , Satyanarayana Rao Manchanahalli R 
Published: September 2020

ABSTRACTLong non-coding RNA has emerged as a key regulator of myriad gene functions. One such lncRNA mrhl, reported by our group, was found to be a regulator ofSOX8, Wnt-signalling along with an important role in embryonic development in mouse. Recently, its human homolog, human mrhl (Hmrhl) was uncovered and study revealed its differential expression in several type of cancers, notably leukemia. In the present study, we further characterize molecular features of lncRNA Hmrhl and gain insight into its functional role in leukemia by gene silencing and transcriptome-based studies. Results indicate its high expression in CML patient samples as well as in K562 cell line. Silencing experiments suggest role of Hmrhl in cell proliferation, migration & invasion in K562 cells. RNA-seq and ChiRP-seq data analysis further revealed its association with important biological processes, including perturbed expression of crucial TFs and cancer-related genes. Among them ZIC1, PDGRFβ and TP53 were identified as regulatory targets, with high possibility of triplex formation by Hmrhl at their promoter site. In addition, we also found TAL-1 to be a potential regulator of Hmrhl expression in K562 cells. Thus, we hypothesize that Hmrhl lncRNA may play a significant role in the pathobiology of CML.
beta-blocker reverses inhibition of beta-2 adrenergic receptor resensitization by hypoxia
Authors: Sun Yu , Gupta Manveen K. , Stenson Kate , Mohan Maradumane L. , Wanner Nicholas , Asosingh Kewal , Erzurum Serpil , Naga Prasad Sathyamangla V. 
Published: September 2020

AbstractIschemia/hypoxia is major underlying cause for heart failure and stroke. Although beta-adrenergic receptor (βAR) is phosphorylated in response to hypoxia, less is known about the underlying mechanisms. Hypoxia results in robust GRK2-mediated β2AR phosphorylation but does not cause receptor internalization. However, hypoxia leads to significant endosomal-β2AR phosphorylation accompanied by inhibition of β2AR-associated protein phosphatase 2A (PP2A) activity impairing resensitization. Phosphoinositide 3-kinase γ (PI3Kγ) impedes resensitization by phosphorylating endogenous inhibitor of protein phosphatase 2A, I2PP2A that inhibits PP2A activity. Hypoxia increased PI3Kγ activity leading to significant phosphorylation of I2PP2A resulting in inhibition of PP2A and consequently resensitization. Surprisingly, β-blocker abrogated hypoxia-mediated β2AR phosphorylation instead of phosphorylation in normoxia. Subjecting mice to hypoxia leads to significant cardiac dysfunction and β2AR phosphorylation showing conservation of non-canonical hypoxia-mediated pathway in vivo. These findings provide mechanistic insights on hypoxia-mediated βAR dysfunction which is rescued by β-blocker and will have significant implications in heart failure and stroke.
Antibiotic resistance genes and mobile genetic elements removal from treated wastewater by sewage-sludge biochar and iron-oxide coated sand
Authors: Calderón-Franco David , Seeram Apoorva , Medema Gertjan , van Loosdrecht Mark C. M. , Weissbrodt David G. 
Published: September 2020

AbstractDisinfection of treated wastewater in wastewater treatment plants (WWTPs) is used to minimize emission of coliforms, pathogens, and antibiotic resistant bacteria (ARB) in the environment. However, the fate of free-floating extracellular DNA (eDNA) that do carry antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) is overlooked. Water technologies are central to urban and industrial ecology for sanitation and resource recovery. Biochar produced by pyrolysis of sewage sludge and iron-oxide-coated sands recovered as by-product of drinking water treatment were tested as adsorbents to remove ARGs and MGEs from WWTP effluent. DNA adsorption properties and materials applicability were studied in batch and up-flow column systems at bench scale. Breakthrough curves were measured with ultrapure water and treated wastewater at initial DNA concentrations of 0.1-0.5 mg mL-1and flow rates of 0.1-0.5 mL min-1. Batch tests with treated wastewater indicated that the adsorption profiles of biochar and iron-oxide coated sand followed a Freundlich isotherm, suggesting a multilayer adsorption of nucleic acids. Sewage-sludge biochar exhibited higher DNA adsorption capacity (1 mg g-1) and longer saturation breakthrough times (4 to 10 times) than iron-oxide coated sand (0.2 mg g-1). The removal of a set of representative ARGs and MGEs was measured by qPCR comparing the inlet and outlet of the plug-flow column fed with treated wastewater. ARGs and MGEs present as free-floating eDNA were adsorbed by sewage-sludge biochar at 85% and iron-oxide coated sand at 54%. From the environmental DNA consisting of the free-floating extracellular DNA plus the intracellular DNA of the cells present in the effluent water, 97% (sewage-sludge biochar) and 66% (iron-oxide coated sand) of the tested genes present were removed. Sewage-sludge biochar displayed interesting properties to minimize the spread of antimicrobial resistances to the aquatic environment while strengthening the role of WWTPs as resource recovery factories.Graphical abstractHighlightsSewage-sludge biochar and iron oxide coated sands were tested to adsorb DNA and cells.Biochar removed 97% of genes tested from environmental DNA of unfiltered effluent.85% of ARGs and MGEs of free-floating extracellular DNA were retained by biochar.Biochar is a WWTP by-product that can be re-used for public health sanitation.
The IgG3 Subclass of β1-adrenergic receptor autoantibody is an endogenous biaser of β1AR signaling
Authors: Mohan Maradumane L. , Nagatomo Yuji , Mukherjee Sromona D. , Engelman Timothy , Morales Rommel , Tang W.H. Wilson , Naga Prasad Sathyamangla V. 
Published: September 2020

ABSTRACTAutoantibodies recognizing human β1ARs generated due to dysregulation in autoimmune response are generally associated with deleterious cardiac outcomes. However, cellular studies show that isolates of β1AR autoantibody from patients differentially modulate β1AR function. β1AR autoantibodies belong to the IgG class of immunoglobulins, however it is not known whether the IgG sub-classes mediate variability in β1AR responses. To determine whether the IgG3 subclass of β1AR autoantibodies uniquely modulate β1AR function, HEK293 cells stably expressing human β1ARs were utilized. Treatment of cells with IgG3(-) serum resulted in significant increase of cAMP compared to IgG3(+) serum. Pre-treatment of cells with IgG3(+) serum impaired dobutamine-mediated Adenylate Cyclase (AC) activity and cAMP generation whereas, it surprisingly increased AC activity and cAMP generation with β-blocker metoprolol. Consistently, purified IgG3(+) β1AR autoantibodies impaired dobutamine-mediated cAMP while elevating metoprolol-mediated AC activity and cAMP. Despite IgG3(+) autoantibodies reducing cAMP response to dobutamine, they mediate significant ERK activation upon dobutamine. IgG3(+) β1AR autoantibodies did not alter β2AR function, reflecting their specificity. The study shows that IgG3(+) β1AR autoantibody impairs agonist-mediated G-protein coupling while preferentially mediating G-protein-independent ERK activation. Furthermore, it uniquely biases β-blocker towards G-protein coupling. This unique biasing capabilities of IgG3(+) β1AR autoantibodies may underlie the beneficial outcomes in patients.
ESCargo: a regulatable fluorescent secretory cargo for diverse model organisms
Authors: Casler Jason C. , Zajac Allison L. , Valbuena Fernando M. , Sparvoli Daniela , Jeyifous Okunola , Turkewitz Aaron P. , Horne-Badovinac Sally , Green William N. , Glick Benjamin S. 
Published: September 2020

AbstractMembrane traffic can be studied by imaging a cargo protein as it transits the secretory pathway. The best tools for this purpose initially block exit of the secretory cargo from the endoplasmic reticulum (ER), and then release the block to generate a cargo wave. However, previously developed regulatable secretory cargoes are often tricky to use or specific for a single model organism. To overcome these hurdles for budding yeast, we recently optimized an artificial fluorescent secretory protein that exits the ER with the aid of the Erv29 cargo receptor, which is homologous to mammalian Surf4. The fluorescent secretory protein forms aggregates in the ER lumen and can be rapidly disaggregated by addition of a ligand to generate a nearly synchronized cargo wave. Here we term this regulatable secretory protein ESCargo (Erv29/Surf4-dependentSecretoryCargo) and demonstrate its utility not only in yeast cells, but also in cultured mammalian cells,Drosophilacells, and the ciliateTetrahymena thermophila. Kinetic studies indicate that rapid transport out of the ER requires recognition by Erv29/Surf4. By choosing an appropriate ER signal sequence and expression vector, this simple technology can likely be used with many model organisms.
15-PGDH Inhibition Activates the Splenic Niche to Promote Hematopoietic Regeneration
Authors: Smith Julianne N.P. , Dawson Dawn M. , Christo Kelsey F. , Jogasuria Alvin P. , Cameron Mark J. , Antczak Monika I. , Ready Joseph M. , Gerson Stanton L. , Markowitz Sanford D. , Desai Amar B. 
Published: September 2020

AbstractThe splenic microenvironment regulates hematopoietic stem and progenitor cell (HSPC) function, particularly during demand-adapted hematopoiesis, however practical strategies to enhance splenic support of transplanted HSPCs have proven elusive. We have previously demonstrated that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using the small molecule (+)SW033291 (PGDHi), increases bone marrow (BM) prostaglandin E2 (PGE2) levels, expands HSPC numbers, and accelerates hematologic reconstitution following BM transplantation (BMT) in mice. Here we demonstrate that the splenic microenvironment, specifically 15-PGDH high-expressing macrophages (MΦs), megakaryocytes (MKs), and mast cells (MCs), regulates steady-state hematopoiesis and potentiates recovery after BMT. Notably, PGDHi-induced neutrophil, platelet, and HSPC recovery were highly attenuated in splenectomized mice. PGDHi induced non-pathologic splenic extramedullary hematopoiesis at steady-state, and pre-transplant PGDHi enhanced the homing of transplanted cells to the spleen. 15-PGDH enzymatic activity localized specifically to MΦs, MK lineage cells, and MCs, identifying these cell types as likely coordinating the impact of PGDHi on splenic HSPCs. These findings suggest that 15-PGDH expression marks novel HSC niche cell types that regulate hematopoietic regeneration. Therefore, PGDHi provides a well-tolerated strategy to therapeutically target multiple HSC niches and to promote hematopoietic regeneration and improve clinical outcomes of BMT.
PEA polymer-coated nanotopography delivers solid-state BMP2, enhances mesenchymal stem cell adhesion, prevents bacterial biofilm formation and protects cells from quorum sensing virulence factors
Authors: Damiati Laila A. , Tsimbouri Monica P. , Ginty Mark , Hernandez Virginia Llopis , Childs Peter , Jayawarna Vineetha , Xiao Yinbo , Burgess Karl , Wells Julia , Sprott Mark R. , Meek R.M. Dominic , Li Peifeng , Oreffo Richard O.C. , Nobbs Angela , Ramage Gordon , Su Bo , Salmeron-Sanchez Manuel , Dalby Matthew J. 
Published: September 2020

AbstractPost-operative infection is a major complication in patients recovering from orthopaedic surgery. As such, there is a clinical need to develop biomaterials for use in regenerative surgery that can promote mesenchymal stem cell (MSC) osteospecific differentiation and that can prevent infection caused by biofilm-forming pathogens. Nanotopographical approaches to pathogen control are being identified, including in orthopaedic materials such as titanium and its alloys. These topographies use high aspect ratio nanospikes or nanowires to prevent bacterial adhesion but these features puncture adhering cells, thus also reducing MSC adhesion. Here, we use a poly(ethyl acrylate) (PEA) polymer coating on titanium nanowires to spontaneously organise fibronectin (FN) and to deliver bone morphogenetic protein 2 (BMP2) to enhance MSC adhesion and osteospecific signalling. This nanotopography when combined with the PEA coating enhanced osteogenesis and reduced adhesion ofPseudomonas aeruginosain culture. Using a novel MSC–Pseudomonas aeruginosaco-culture, we also show that the coated nanotopographies protect MSCs from cytotoxic quorum sensing and signalling molecules. We conclude that the PEA polymer-coated nanotopography can both support MSCs and prevent pathogens from adhering to a biomaterial surface, thus protecting from biofilm formation and bacterial infection and supporting osteogenic repair.
Experimental Evolution ofPseudomonas putidaunder Silver Ion versus Nanoparticle Stress
Authors: Dong Feng , Quevedo Ana C. , Wang Xiang , Valsami-Jones Eugenia , Kreft Jan-Ulrich 
Published: September 2020

SummaryWhether the antibacterial properties of silver nanoparticles (AgNPs) are simply due to the release of silver ions (Ag+) or, additionally, nanoparticle-specific effects, has been debated for over a decade. We used experimental evolution of the model environmental bacteriumPseudomonas putidato ask whether bacteria respond differently to Ag+or AgNP treatment. We pre-evolved five cultures of strain KT2440 for 70 d without Ag to reduce confounding adaptations before dividing the fittest pre-evolved culture into five cultures each, evolving in the presence of low concentrations of Ag+, well-defined AgNPs or Ag-free controls for a further 75 d. The mutations in the Ag+or AgNP evolved populations displayed different patterns that were statistically significant. The non-synonymous mutations in AgNP-treated populations were mostly associated with cell surface proteins, including cytoskeletal membrane protein (FtsZ), membrane sensor and regulator (EnvZ and GacS) and periplasmic protein (PP_2758). In contrast, Ag+treatment selected for mutations linked to cytoplasmic proteins, including metal ion transporter (TauB) and those with metal binding domains (ThiL and PP_2397). These results suggest the existence of AgNP-specific effects, either caused by sustained delivery of Ag+from AgNP-dissolution, more proximate delivery from cell-surface bound AgNPs, or by direct AgNP action on the cell’s outer membrane.Originality-Significance StatementThe increasing use of silver nanoparticles (AgNPs) and their release into the environment may affect environmental microorganisms and their communities and evolution. It has long been debated whether the toxicity of AgNPs towards microorganisms is solely due to their dissolution into toxic Ag+or whether distinct nanoparticle related toxicity exists. We set up an evolution experiment to explore the adaptation of the environmental model bacteriumPseudomonas putidato Ag+versus AgNP stress in order to elucidate the potentially different toxicity mechanisms of ionic and nanoparticulate Ag. We found novel mutations and distinct mutation patterns under Ag+and AgNP treatment by whole genome sequencing. Our work highlights the association of the mutations selected by Ag+stress with metal ion metabolism inside the cells and the mutations specific to AgNP stress with the cell’s surface. The finding thatP. putidacells evolved in different directions under selection by Ag+and AgNPs demonstrates a need for assessing the toxicity of nanomaterials separately in any environmental risk assessments.
Matrix metalloproteinases and tissue inhibitors of metalloproteinases in murine coronavirus-induced neuroinflammation
Authors: Sengupta Sourodip , Addya Sankar , Biswas Diptomit , Sarma Jayasri Das 
Published: September 2020

AbstractMouse hepatitis virus (MHV) belongs to the same beta-coronavirus family as SARS-CoV-2, MERS-CoV, and SARS-CoV. Studies have shown the requirement of host cellular proteases for priming the surface spike protein during viral entry and transmission in coronaviruses. The metzincin family of metal-dependent endopeptidases called matrix metalloproteinases (MMPs) is involved in virus encephalitis, enhanced blood-brain barrier permeability, or cell-to-cell fusion upon viral infection. Here we show the role of MMPs as mediators of virus-induced host neuroinflammatory response in the MHV model. Infection of mice with wild-type MHV-A59 or its isogenic recombinant strains, RSA59 or RSMHV2 significantly upregulated MMP-3, MMP-8, and MMP-14 transcript levels. Functional network assessment with Ingenuity Pathway Analysis revealed a direct involvement of these MMPs in disrupting junctional assembly between endothelial cells via interaction with junctional adhesion molecules and thereby facilitating transmigration of peripheral lymphocytes. Our findings also suggest mRNA upregulation of Park7, which is involved in NADPH oxidase-dependent ROS production, following RSA59 infection. RSA59 infection resulted in elevated mRNA levels of RelA, a subunit of NF-κB. Infection with MHV-A59 is known to generate ROS, and oxidative stress can activate NF-κB. Thus, our findings indicate the existence of a possible nexus between ROS, NF-κB, and MMPs in RSA59-induced neuroinflammation. We also assessed the expression of endogenously produced regulators of MMP activities. Elevated mRNA and protein levels of tissue inhibitors of metalloproteinases 1 (TIMP-1) in MHV-A59 infection are suggestive of a TIMP-1 mediated host antiviral response.ImportanceThe newly emergent coronavirus has brought the world to a near standstill. In the past, studies have focused on the function of host proteases in virus attachment and entry. Our research indicates the involvement of a group of metal-dependent host proteases in inflammation associated with coronavirus infection. Inflammation is the first response of the host to virus infection. While it helps in restricting the spread and clearance of viral particles, uncontrolled inflammation results in several inflammatory consequences. Therefore, it becomes vital to limit unchecked host immune response. The inhibition of specific metalloproteases represents a potential new therapeutic approach in coronavirus infection and disease outcome.
Clinical characteristics of children with COVID-19 admitted in a tertiary referral center in Perú
Authors: Chilet Christian Chiara , Vilchez Medalit Luna , Afaray Julio Maquera , Mesones Blanca Salazar , Alvarez Diana Portillo , Miranda Ramiro Priale , Mendoza Franklin , Munayco Aldo , Baca Jenny , Santiago Mitsi , López Jose W. 
Published: September 2020

AbstractIntroductionCOVID-19 pandemic represents a big impact on children’s health, this study describes the behavior of the disease in hospitalized pediatric patients in the Instituto Nacional de Salud del Niño San Borja (INSN-SB).MethodsRetrospective study of patients with confirmed COVID-19 diagnostic between March and July 2020. Demographic, clinic, laboratory, radiology and treatment data were collected and for the analysis descriptive statistics were included.ResultsFrom a total of 91 patients. 36.3% (33) were female. The age group who was affected the most were school children with a median age of 4 years old (IQR 1-8). Patients who came from Lima represented 61.5%. Previous contact was determined in 30.8% of the cases. PCR results for SARS CoV-2 were positive in 50.6% of the cases and 49.4% in the quick tests. Comorbidity was present in 53.8% of the cases. Most frequent symptoms were fever (39.6%), general discomfort (23.1%), cough (19.8%) and shortness of breath (14.3%). Presence of MIS-C was confirmed in 6 patients. Use of antibiotics represented 76.9% of the cases. The most frequent radiology pattern was bilateral interstitial (57.7%). Comorbidities were present in 68.2% (15/22) of patients in PICU. From a total of 9 deceased patients, 6 were admitted in PICU and 8 presented associated comorbidities.ConclusionsCOVID-19 in children displays mild and moderate clinical manifestations. A great proportion of patients exhibited comorbidities, especially PICU patients and the ones that died.What is known about the subjectIn pediatric patients, the prevalence and severity of COVID-19 are usually low, however, in the presence of MIS-C, greater severity and probability of admission to the PICU is observed.What this study adds-This study describes the results of complex pediatric patients and the associated comorbidity in LMIC setting that showed greater severity and admission to the ICU.-Microbiological isolates in cultures were low, therefore the initiation of empirical antibiotic therapy is not justified in most cases.