bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19 pediatric mortality rates are heterogeneous between countries
Authors: González-García Nadia , Miranda-Lora América Liliana , Garduño-Espinosa Juan , Granados-Riverón Javier T. , Méndez-Galván Jorge Fernando , Nieto-Zermeño Jaime , Castilla-Peón María F
Published: September 2020

Introduction

Severe COVID-19 is infrequent in children, with a lethality rate of about 0.08%. This study aims to explore differences in the pediatric mortality rate between countries.

Methods

Countries with populations over 5 million that report COVID-19 deaths disaggregated data by quinquennial or decennial age groups were analyzed. Data were extracted from COVID-19 Cases and Deaths by Age Database, national ministries of health, and the World Health Organization.

Results

23 countries were included in the analysis. Pediatric mortality varied from 0 to 12.1 deaths per million people of the corresponding age group, with the highest rate in Peru. In most countries, deaths were more frequent in the 0-4 years old age group, except for Brazil. The pediatric/ general COVID-19 mortality showed a great variation between countries and ranged from 0 (Republic of Korea) to 10.4% (India). Pediatric and Pediatric/general COVID mortality have a strong correlation with 2018 neonatal mortality (r=0.77, p<0.001 and r= 0.88, p<0.001 respectively), while it has a moderate or absent (r=0.47, p=0.02 and r=0.19, p=0.38, respectively) correlation with COVID-19 mortality in the general population.

Conclusions

There is an important heterogenicity in pediatric COVI-19 mortality between countries that parallels historical neonatal mortality. Neonatal mortality is a known index of the quality of a country’s Health System which points to the importance of social determinants of health in pediatric COVID-19 mortality disparities, an issue which should be further explored.
Investigating the implications of COVID-19 for the rural and remote population of Northern Ontario using a mathematical model
Authors: Savage DW , Fisher A , Choudhury S , Ohle R , Strasser RP , Orkin A , Mago V
Published: September 2020

Background

COVID-19 has the potential to disproportionately affect the rural, remote, and Indigenous populations who typically have a worse health status and live in substandard housing, often with overcrowding. Our aim is to investigate the potential effect of COVID-19 on intensive care unit (ICU) resources and mortality in northwestern Ontario.

Methods

This study was conducted in northwestern Ontario which has a population of 230,000. A set of differential equations were used to represent a modified Susceptible-Infectious-Recovered (SIR) model with urban and rural hospital resources (i.e., ICU and hospital beds). Rural patients requiring ICU care flowed into the urban ICU. Sensitivity analyses were used to investigate the effect of poorer health status (i.e., increased hospital admission, ICU admission, and mortality) and overcrowding (i.e., increased contact rate) in the rural population as compared to the urban population. Physical distancing within the urban population was modelled as a decreased contact rate.

Results

At the highest contact rate, the peak in daily active cases, ICU bed requirements and mortality was higher and occurred earlier than lower contact rates. The urban population with a lower contact rate and baseline health status had a lower predicted prevalence of active cases and lower mortality than the rural population.

Interpretation

An increased contact rate and worse health status in the rural population will likely increase the required ICU resources and mortality as compared to the urban population. Rural populations will likely be affected disproportionately more than urban populations.
On Topological Properties of COVID-19: Predicting and Controling Pandemic Risk with Network Statistics
Authors: So Mike K.P. , Chu Amanda M.Y. , Tiwari Agnes , Chan Jacky N.L.
Published: September 2020

The spread of coronavirus disease 2019 (COVID-19) has caused more than 24 million confirmed infected cases and more than 800,000 people died as of 28 August 2020. While it is essential to quantify risk and characterize transmission dynamics in closed populations using Susceptible-Infection-Recovered modeling, the investigation of the effect from worldwide pandemic cannot be neglected. This study proposes a network analysis to assess global pandemic risk by linking 164 countries in pandemic networks, where links between countries were specified by the level of ‘co-movement’ of newly confirmed COVID-19 cases. More countries showing increase in the COVID-19 cases simultaneously will signal the pandemic prevalent over the world. The network density, clustering coefficients, and assortativity in the pandemic networks provide early warning signals of the pandemic in late February 2020. We propose a preparedness pandemic risk score for prediction and a severity risk score for pandemic control. The preparedness risk score contributed by countries in Asia is between 25% to 50% most of the time after February and America contributes close to 50% recently. The high preparedness risk contribution implies the importance of travel restrictions between those countries. The severity risk score of America is greater than 50% after May and even exceeds 75% in July, signifying that the control of COVID-19 is still worrying in America. We can keep track of the pandemic situation in each country using an online dashboard to update the pandemic risk scores and contributions.
The Peak of COVID-19 in India
Authors: Yadav Suryakant , Yadav Pawan Kumar
Published: September 2020

Introduction

Following the USA, India ranks the second position in the world for COVID-19 cases with the highest number of daily confirmed cases since September 2020. The peak of COVID-19 cases is the most warranted feature for understanding the curvature of COVID-19 cases.

Aim

This study aims to analyse the growth rates of the daily confirmed cases and to provide an expected count of the peak of daily confirmed cases.

Data

We retrieved data from an Application Programming Interface portal https://www.covid19india.org/ which is open access and publicly available.

Methods

Exponential model was applied to estimate the growth rates of daily confirmed cases. The estimated growth rates were used for calculating the doubling time. The Lotka-Euler method was applied to calculate the effective reproduction rate. SARIMA model was developed for the growth rates to predict daily confirmed cases.

Results

Results show the best fit of the exponential model over the daily confirmed cases. The growth rates estimated from the exponential model shows an unsteady, modest decline. Doubling time shows a linear increase. The effective reproduction rate declined from 3.6 persons in the third week of March 2020 to 1.14 persons at the end of August 2020 and 1.12 persons in the mid-September 2020. The diagnosis of the developed SARIMA model confirmed no trends in the residuals, no outliers, and nearly constant variance. The forecast suggests the peak value of daily confirmed cases would waver around 105,000 counts in the third week of September 2020. The cumulative COVID-19 cases would account for approximately 105 lakhs at the end of December 2020.

Conclusion

The exponential model unravels a shift and a modest decline in the growth of daily confirmed cases. The trends in R(t) show analogue with the trends in growth rates of daily confirmed cases. The study shows that the SARIMA model is suitable for projecting daily confirmed cases. The results shed light on the understanding of the trends and epidemiological stage of COVID-19 disease, in the cognisance of the peak.

Contribution

This study based on moments of the distribution of the daily confirmed cases of COVID-19 disease unravels the uncertainty about the peak and curvature of COVID-19 disease.

Research Highlights

The exponential model is the best fit over daily confirmed COVID-19 cases.

The trends in growth rates of daily confirmed cases show a swift decline during the five-and-a-half months period since April 2020.

The effective reproduction rate in India declined from 3.6 persons in the third week of March 2020 to 1.14 persons at the end of August 2020 and 1.12 persons in the mid of September 2020.

The forecast reveals that the peak of daily confirmed cases wavers at approximately 105,000 cases since the third week of September 2020.

The R(t) value would be equal to one in the first week of December 2020.

The cumulative confirmed cases of COVID-19 in India would account to approximately 105 lakhs at the end of December 2020.
Dynamics of alternative splicing during somatic cell reprogramming reveals functions for RNA-binding proteins CPSF3, hnRNP UL1 and TIA1
Authors: Vivori Claudia , Papasaikas Panagiotis , Stadhouders Ralph , Di Stefano Bruno , Balaguer Clara Berenguer , Generoso Serena , Mallol Anna , Sardina José Luis , Payer Bernhard , Graf Thomas , Valcárcel Juan
Published: September 2020

In contrast to the extensively studied rewiring of epigenetic and transcriptional programs required for cell reprogramming, the dynamics of post-transcriptional changes and their associated regulatory mechanisms remain poorly understood. Here we have studied the dynamics of alternative splicing (AS) changes occurring during efficient reprogramming of mouse B cells into induced pluripotent stem (iPS) cells. These changes, generally uncoupled from transcriptional regulation, significantly overlapped with splicing programs reported during reprogramming of mouse embryonic fibroblasts (MEFs). Correlation between gene expression of potential regulators and specific clusters of AS changes enabled the identification and subsequent validation of CPSF3 and hnRNP UL1 as facilitators, and TIA1 as repressor of MEFs reprogramming. These RNA-binding proteins control partially overlapping programs of splicing regulation affecting genes involved in developmental and morphogenetic processes. Our results reveal common programs of splicing regulation during reprogramming of different cell types and identify three novel regulators of this process.
The Quorum Sensing Peptide EntF* Promotes Colorectal Cancer Metastasis in Mice: A New Factor in the Microbiome-Host Interaction
Authors: Debunne Nathan , Wynendaele Evelien , Janssens Yorick , De Spiegeleer Anton , Verbeke Frederick , Tack Liesa , Van Welden Sophie , Goossens Evy , Knappe Daniel , Hoffmann Ralf , Van De Wiele Christophe , Laukens Debby , Van Eenoo Peter , Van Immerseel Filip , De Wever Olivier , De Spiegeleer Bart
Published: September 2020

Background

Colorectal cancer, one of the most common malignancies worldwide, is associated with a high mortality rate, mainly caused by metastasis. Comparative metagenome-wide analyses between healthy individuals and cancer patients suggest a role for the human intestinal microbiota. Nevertheless, which microbial molecules are involved in this communication is largely unknown, with current studies mainly focusing on short chain fatty acids and amino acid metabolites as potential mediators. However, quorum sensing peptides are not yet considered in this microbiome-host interaction: theirin vivopresence nor anyin vivohost-effect have been reported.

Results

For the first time, we showed that a quorum sensing peptide metabolite, EntF* produced by intestinal microbiota (E. faecium), is present in the blood circulation of mice. Moreover, it significantly promotes colorectal cancer metastasisin vivo, with metastatic lesions found in both liver and lung tissues, using an orthotopic mice model evaluating bioluminescence as well as macroscopic and microscopic presence of metastatic tumour nodules.In vitrotests on E-cadherin expression levels thereby indicated that the first, second, sixth and tenth amino acid of EntF* were critical for the epithelial-mesenchymal transition (EMT) effect, responsible for tumour metastasis.

Conclusion

This paper adds a new group of molecules, the quorum sensing peptides, as an additional causative factor explaining the microbiome-host interaction. The presence of a selected quorum sensing peptide (metabolite) in the mouse was proven for the first time and itsin vivoeffect on colorectal metastasis was demonstrated. We anticipate ourin vivoresults to be a starting point for broader microbiome-health investigations, not only limited to colorectal cancer metastasis, but also for developing novel bio-therapeutics in other disease areas, giving due attention to the QSP produced by the microbiome.
Cargo receptor-assisted endoplasmic reticulum export of pathogenic α1-antitrypsin polymers
Authors: Ordonez Adriana , Harding Heather P , Marciniak Stefan J , Ron David
Published: September 2020

Circulating polymers of alpha1-antitrypsin (α1AT) are chemo-attractant for neutrophils and contribute to inflammation in pulmonary, vascular and adipose tissues. Cellular factors affecting the intracellular itinerary of mutant polymerogenic α1AT remain obscure. Here, we report on an unbiased genome-wide CRISPR/Cas9 screen for regulators of trafficking of the polymerogenic α1ATH334Dvariant. Single guide RNAs targeting genes whose inactivation enhanced accumulation of polymeric α1AT were enriched by iterative construction of CRISPR libraries based on genomic DNA from fixed cells selected for high polymer content by fluorescence-activated cell sorting. This approach bypassed the limitation to conventional enrichment schemes imposed by cell fixation and identified 121 genes involved in polymer retention at false discovery rate < 0.1. From that set of genes, the pathway ‘cargo loading into COPII-coated vesicles’ was overrepresented with 16 significant genes, including two transmembrane cargo receptors, LMAN1 (ERGIG-53) and SURF4.LMAN1andSURF4-disrupted cells displayed a secretion defect extended beyond α1AT monomers to polymers, whose low-level secretion was especially dependent on SURF4 and correlated with SURF4-α1ATH334Dphysical interaction and with enhanced co-localisation of polymeric α1ATH334Dwith the endoplasmic reticulum (ER). These findings suggest that ER cargo receptors co-ordinate intracellular progression of α1AT out of the ER and modulate the accumulation of polymeric α1AT not only by controlling the concentration of precursor monomers but also through a previously-unrecognised role in secretion of the polymers themselves.
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

Hybridization 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

The 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

Long 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

Ischemia/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

Disinfection 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 abstract

Highlights

Sewage-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

Autoantibodies 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

Membrane 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

The 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

Post-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

Whether 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 Statement

The 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

Mouse 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.

Importance

The 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

Introduction

COVID-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).

Methods

Retrospective 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.

Results

From 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.

Conclusions

COVID-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 subject

In 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

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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.

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Microbiological isolates in cultures were low, therefore the initiation of empirical antibiotic therapy is not justified in most cases.
Feasibility of Community Health Worker based cardiovascular risk reduction strategies in urban slums of Bhopal: Rationale, design and baseline results of community based study
Authors: Pakhare Abhijit , Joshi Ankur , Khadanga Sagar , Kumar Sanjeev , Atal Shubham , Ingle Vaibhav , Sabde Yogesh , Shrivastava Neelesh , Lahiri Anuja , Ranjan Akash , Joshi Rajnish
Published: September 2020

In urban India, about 35-40% of all adults have hypertension and about 10-15% have diabetes mellitus. National Program for Prevention and Control of Diabetes, Cancer and Stroke (NPCDCS) launched by Government of India has envisaged to screen all adults aged 30 years and above for presence of hypertension and diabetes mellitus in the community through population-based screening, initiate positively screened and diagnosed on drug therapy, and follow them up for treatment adherence. In this context, the current study aims to estimate burden of high cardiovascular disease (CVD) risk and to evaluate feasibility of community health workers-based strategies in reducing CVD among adults living in urban slums. We have identified and trained CHWs from within the urban slum communities in Bhopal, in chronic disease identification, skills in self-care and adherence promotion skills. At-risk individuals were linked to public health facilities as outlined under NPCDCS. Primary outcome is assessment of burden of high cardiovascular risk and its determinants. Secondary outcome is feasibility of community health worker-based adherence promotion. Between November 2017 and June 2018, CHWs in 14 urban slum clusters, screened a total of 6178 individuals out of which 4781 (77.43%) attended confirmation camp. Around 2393 (38.8%) were current tobacco users (smoking and/or smokeless), and 4697 (76.1%) has a sedentary lifestyle. Out of 758 (12.3%) known hypertensives, 354 (46.7%) had controlled hypertension whereas out of 333 (5.4%) known diabetes patients, 169 (57.5%) has controlled level of diabetes. In 813 (15%) out of 5416 and 151 (3.4%) out of 4486 adults, hypertension and diabetes was newly detected respectively. Results of this study have a potential to strengthen NPCDCS across all urban areas of the country. This manuscript describes detailed protocol of the study and presents baseline summary of CVD risk factor burden in urban slums of Bhopal.
Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia
Authors: Singh Tarjinder , Neale Benjamin M. , Daly Mark J.
Published: September 2020

By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 - 50, P < 2.14 × 10-6), and 32 genes at a FDR < 5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure, and function of the synapse. The associations of NMDA receptor subunit GRIN2A and AMPA receptor subunit GRIA3 provide support for the dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We find significant evidence for an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD), and severe neurodevelopmental disorders (DD/ID), supporting a neurodevelopmental etiology for schizophrenia. We show that protein-truncating variants in GRIN2A, TRIO, and CACNA1G confer risk for schizophrenia whereas specific missense mutations in these genes confer risk for DD/ID. Nevertheless, few of the strongly associated schizophrenia genes appear to confer risk for DD/ID. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk, suggesting that common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, implying that more schizophrenia risk genes await discovery using this approach.
SARS-CoV-2 antibody seroprevalence in Tbilisi, the capital city of country of Georgia
Authors: Tsertsvadze Tengiz , Gatserelia Lana , Mirziashvili Marine , Dvali Natia , Abutidze Akaki , Metchurtchlishvili Revaz , el Rio Carlos , Chkhartishvili Nikoloz
Published: September 2020

Background

Georgia timely implemented effective response measures, with testing, contact tracing and isolation being the main pillar of the national response, achieving the lowest cumulative incidence of SARS-CoV-2 in the European region.

Methods

We conducted a survey to estimate SARS-CoV-2 IgG antibody seroprevalence among adult residents of capital city of Tbilisi (adult population: 859,328). Participants were recruited through respondent driven sampling during May 18-27, 2020. Blood specimens were tested for SARS-CoV-2 IgG antibodies using commercially available lateral flow immunoassay (COVID-19 IgG/IgM Rapid Test Cassette, Zhejiang Orient Gene Biotech). Crude seroprevalence was weighted by population characteristics (age, sex, district of Tbilisi) and further adjusted for test accuracy.

Results

Among 1,068 adults recruited 963 (90.2%) were between 18 and 64 years-old, 682 (63.9%) women. 176 (16.5%) reported symptoms indicative of SARS-CoV-2 infection occurring in previous three months. Nine persons tested positive for IgG: crude seroprevalence: 0.84%, (95% CI: 0.33%-1.59%), weighted seroprevalence: 0.94% (95% CI: 0.37%-1.95%), weighted and adjusted for test accuracy: 1.02% (95% CI: 0.38%-2.18%). The seroprevalence estimates translate into 7,200 to 8,800 infections among adult residents of Tbilisi, which is at least 20 times higher than the number of confirmed cases.

Conclusions

Low seroprevalence confirms that Georgia successfully contained spread of SARS-CoV-2 during the first wave of pandemic. Findings also suggest that undocumented cases due to asymptomatic or very mild disease account for majority of infections. Given that asymptomatic persons can potentially spread the virus, test and isolate approach should be further expanded to control the epidemic.
Communicating polygenic and non-genetic risk for atherosclerotic cardiovascular disease - An observational follow-up study
Authors: Widén Elisabeth , Junna Nella , Ruotsalainen Sanni , Surakka Ida , Mars Nina , Ripatti Pietari , Partanen Juulia J , Aro Johanna , Mustonen Pekka , Tuomi Tiinamaija , Palotie Aarno , Salomaa Veikko , Kaprio Jaakko , Partanen Jukka , Hotakainen Kristina , Pöllänen Pasi , Ripatti Samuli
Published: September 2020

Background

Algorithms including both traditional risk factors and polygenic risk scores (PRS) can significantly improve prediction of atherosclerotic cardiovascular disease (ASCVD). However, the clinical benefit of adding PRS to clinical risk evaluation remains unclear.

Objectives

The study evaluated the attitudes of 7,342 individuals (64% women, mean age 56 yrs) upon receiving personal genome-enhanced ASCVD risk information, and prospectively assessed the impact on the participants’ health behavior.

Methods

The participant’s 10-year risk for ASCVD was estimated using both a traditional clinical risk score and a PRS-enhanced score, and both scores were communicated directly to study participants with an interactive web-tool.

Results

When reassessed after 1.5 years by a clinical visit and questionnaires, 20.8% of individuals at high (>10%) ASCVD risk had seen a doctor, 12.4% reported weight loss, 14.2% of smokers had quit smoking, and 15.4% had signed up for health coaching online. Altogether, 42.6% of individuals at high risk had made some health behavioral change compared to 33.5% of persons at low/average risk such that a higher baseline risk predicted a favorable change (p<0.001), with both clinical (p<0.001) and genomic factors (p=0.003) contributing independently. Seeing a doctor and weight loss both resulted in clinically significant improvement of lipid profiles (lower LDL-cholesterol and triglycerides) and lower systolic blood pressure (p<0.01).

Conclusions

Web-based communication of personal ASCVD risk-data including polygenic risk to middle-aged persons can motivate positive changes in health behavior. It supports integration of genomic information into clinical risk calculators as a feasible approach to enhance disease prevention.

Condensed Abstract

Prediction tools that combine polygenic risk scores (PRS) with clinical factors provide a new opportunity for improved risk assessment and prevention of atherosclerotic cardiovascular disease (ASCVD), but the clinical impact of PRS has hitherto remained unclear. We evaluated the longitudinal effects of using a web-based tool to communicate genome-based ASCVD risk-information to 7,342 middle-aged individuals. 42% of persons at high risk improved their health behavior during follow-up which resulted in clinically significant improvement of lipid profiles and lower systolic blood pressure. This supports integration of PRS into clinical risk calculators as a feasible approach to enhance disease prevention.