bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulatory role of sphingolipid metabolites, sphingosine-1-phosphate and C16:0 ceramide, in immunogenic cell death of colon cancer cells induced by Bak/Bax-activation
Authors: Hengst Jeremy A. , Nduwumwami Asvelt J. , Yun Jong K.
Published: September 2021

We have previously identified sphingolipid metabolism as a key intracellular process associated with immunogenic cell death (ICD) induced by mitoxantrone in colon cancer cells. Specifically, we have demonstrated that inhibition of the sphingosine kinases (SphKs) synergistically enhanced production of hallmarks of ICD including ectoCRT production. To better understand the mechanism associated with ICD enhanced by SphK1-inhibition, we focused on the ER stress-associated intracellular signaling pathways leading to ectoCRT production. It is known that ABT-263 and AZD-5991 (ABT/AZD) are inhibitors of Bcl-2/Bcl-XL and MCL-1, respectively, leading to activation of Bak/Bax. Herein, we now provide evidence that treatment of DLD-1 colon cancer cells with ABT/AZD results in the production of ectoCRT indicative of ICD. Additionally, our data show that ABT/AZD-induced ectoCRT production is significantly enhanced by combination treatment with the SphK1 inhibitor, PF-543. Mechanistically, we demonstrate that combined treatment of ABT/AZD+PF-543 induces ectoCRT exposure in a caspase 8-dependent manner. Accordingly, we have identified a Bak/Bax activation-dependent pathway that leads to activation of a pro-survival SphK1/sphingosine-1-phosphate (S1P) signaling that attenuates ectoCRT production. Additionally, we have identified a regulatory role of ceramide synthase 6 (CerS6)- C16:0 Cer in transporting of dimeric CRT to the cell surface (ectoCRT). Together, these results indicate that sphingolipid metabolites, such as S1P and C16:0 Cer, have a key regulatory role for survival/death decisions of cancer cells in response to ICD-inducing chemotherapeutic agents such as mitoxantrone and ABT/AZD. Hence, targeting SphKs may be an innovative means to enhance the efficacy of ICD-inducing chemotherapeutic agents promoting anti-tumor innate/adaptive immune response since SphK inhibition blocks the anti-ICD effects of S1P while simultaneously accumulating sphingosine (Sph) leading to pro-ICD C16:0 Cer synthesis.
Modeling the levels, trends, and connectivity of malaria transmission using genomic data from a health facility in Thiès, Senegal
Authors: Lee Albert , Ndiaye Yaye Die , Badiane Aida , Deme Awa , Daniels Rachel F. , Schaffner Stephen F. , Fall Fatou Ba , Ndiop Médoune , Gueye Alioune Badara , Diallo Ibrahima , Battle Katherine E. , Wenger Edward A. , Bever Caitlin A. , Sene Doudou , MacInnis Bronwyn , Wirth Dyann F. , Ndiaye Daouda , Hartl Daniel L. , Volkman Sarah K. , Proctor Joshua L.
Published: September 2021

Molecular data and analysis outputs are being integrated into malaria surveillance efforts to provide valuable programmatic insights for national malaria control programs (NMCPs). A plethora of studies from diverse geographies have demonstrated that malaria parasite genetic data can be an important tool for drug resistance monitoring, species identification, outbreak analysis, and transmission characterization. Despite many successful research efforts, there are still important knowledge gaps hindering practical translation of each of these use cases for NMCPs. Here, we leverage epidemiological modeling and time-series data of 2035 genetic sequences collected in Thiès, Senegal from 2006-2018 to provide a quantitative and setting-specific assessment of the levels, trends, and connectivity of malaria transmission. We also identify the genetic features that are the most informative for inferring transmission in Thiès, such as the fraction of the population with multiple infections and the persistence of parasite lineages across multiple transmission seasons. The model fitting and uncertainty quantification framework also reveals a significant decrease in the level of malaria transmission around 2013. This difference coincides with a large-scale drought and bed net campaign by the NMCP and USAID and is independently corroborated by geo-spatial models of incidence in Thiès. We find that genetically identical samples are more likely to be geographically clustered even at the neighborhood scale; and moreover, these lineages propagate non-randomly around the city. Our approach and results provide quantitative guidance for the interpretation of malaria parasite genetic data from Thiès, Senegal and indicates the value of increased malaria genomic surveillance for NMCPs.
Public perception of organ donation and transplantation policies in Southern Spain
Authors: Díaz-Cobacho Gonzalo , Cruz-Piqueras Maite , Delgado Janet , Hortal-Carmona Joaquín , Martínez-López M. Victoria , Molina-Pérez Alberto , Padilla-Pozo Álvaro , Ranchal-Romero Julia , Rodríguez-Arias David
Published: September 2021

Background

This research explores how public awareness and attitudes towards donation and transplantation policies may contribute to Spain’s success in cadaveric organ donation.

Materials and Methods

A representative sample of 813 people residing in Andalusia (Southern Spain) were surveyed by telephone or via Internet between October and December 2018.

Results

Most participants trust Spain’s donation and transplantation system (93%) and wish to donate their organs after death (76%). Among donors, a majority have expressed their consent (59%), while few non-donors have expressed their refusal (14%). Only a minority is aware of the presumed consent system in force (28%) and feel sufficiently informed regarding the requirements needed to be an organ donor (16%). Participants mainly consider that relatives should represent the deceased’s preferences and be consulted when the deceased’s wishes are unknown, as is the case in Spain.

Conclusions

Public trust in the transplant system may contribute to Spain’s high performance in organ donation. High levels of societal support towards organ donation and transplantation do not correspond in Spain with similar levels of public awareness of donation and transplantation policies.
Evaluation of evidence for pathogenicity demonstrates thatBLK, KLF11andPAX4should not be included in diagnostic testing for MODY
Authors: Laver Thomas W , Wakeling Matthew N , Knox Olivia , Colclough Kevin , Wright Caroline F , Ellard Sian , Hattersley Andrew T , Weedon Michael N , Patel Kashyap A
Published: September 2021

Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant form of monogenic diabetes, reported to be caused by variants in 16 genes. Concern has been raised about whether variants inBLK(MODY11),KLF11(MODY7) andPAX4(MODY9) cause MODY. We examined variant-level genetic evidence (co-segregation with diabetes and frequency in population) for published putative pathogenic variants in these genes and used burden testing to test gene-level evidence in a MODY cohort (n=1227) compared to population control (UK Biobank, n=185,898). For comparison we analysed well-established causes of MODY,HNF1AandHNF4A. The published variants inBLK, KLF11andPAX4showed poor co-segregation with diabetes (combined LOD scores ≤1.2), compared toHNF1AandHNF4A(LOD scores >9), and are all too common to cause MODY (minor allele frequency >4.95×10−5). Ultra-rare missense and protein-truncating variants (PTVs) were not enriched in a MODY cohort compared to the UK Biobank (PTVsP>0.05, missenseP>0.1 for all three genes) whileHNF1AandHNF4Awere enriched (P<10−6). Sensitivity analyses using different population cohorts supported our results. Variant and gene-level genetic evidence does not supportBLK, KLF11orPAX4as causes of MODY. They should not be included in MODY diagnostic genetic testing.
CanIsoNet: A Database to Study the Functional Impact of Isoform Switching Events in Diseases
Authors: Karakulak Tülay , Szklarczyk Damian , Saylan Cemil Can , Moch Holger , von Mering Christian , Kahraman Abdullah
Published: September 2021

Motivation

Alternative splicing, as an essential regulatory mechanism in normal mammalian cells, is frequently disturbed in cancer and other diseases. Switches in the expression of most dominant alternative isoforms can alter protein interaction networks of associated genes giving rise to a disease or disease progression. Here, we present CanIsoNet (disease-specific isoform interaction network), a database to view, browse and search these isoform switching events. CanIsoNet is the first webserver that incorporates isoform expression data with STRING interaction networks and ClinVar annotations to predict the pathogenic impact of isoform switching events in various diseases.

Results

Data in CanIsoNet can be browsed by disease or searched by genes or isoforms in annotation-rich data tables. Various annotations for 11,072 isoforms and 13,531 unique isoform switching events across 28 different tissue types are provided. The network density score for each disease-specific isoform, PFAM domain IDs of disrupted interactions, domain structure visualization of transcripts and expression data of switched isoforms for each sample are given. Additionally, the genes annotated in ClinVar are highlighted in the interactive interaction network.

Availability

CanIsoNet is freely available at https://caniso.net. The source codes can be found under a Creative Common License at https://github.com/kahramanlab/CanIsoNet_Web.

Supplementary Information

Supplementary data are available at Bioinformatics online.
Prevalence of Antimicrobial Residues in Tissues of Broilers Sold at a Local Market in Enugu State, Nigeria Using the European Four Plate Test
Authors: Onwumere-Idolor O. S. , Ogugua A. J. , Ezenduka E. V. , Nwanta J. A. , Anaga A.
Published: September 2021

Background

Consumption of animal tissues treated with antimicrobial agents may be deleterious if they contain violative levels of the residues. This study determined antimicrobial residues prevalence in broilers sold at Ikpa market, Nsukka, Nigeria.

Methods

Tissues from muscle, liver and kidney of 60 commercial broilers (180 samples) were tested for antimicrobial residues using the conventional Four Plate Test.

Result

Prevalence of 80.0% (48/60) and 51.7% (93/180) was recorded in the birds and samples {muscle 40.0%(24/60); liver 55.0%(33/60) and kidney 60.0%(36/60)} respectively. There was no significant association between residue occurrence and tissue type (χ2 (2) = 5.206; p = 0.074). Possible antimicrobial classes detected were: macrolid (50.0%) at pH 8.0 with Micrococcus luteus; β-lactams and tetracyclines (64.4%) with Bacillus subtillis at pH 6.0; sulphonamides (53.3%) at pH 7.2 with Bacillus subtillis, and aminoglycosides (46.8%) at pH 8.0 with Bacillus subtillis. Twenty-four tissue samples were positive at all four pH levels indicating use of more than one class of antimicrobials during each treatment.

Conclusion

Antimicrobial residues were detected in commercial broilers (muscles, liver and kidney) sampled at Ikpa Market, Nsukka. This is of public health importance given that antimicrobial residues are not monitored in poultry consumed in Nigeria.
Identifying At-Risk Communities and Key Vulnerability Indicators in the COVID-19 Pandemic
Authors: Thais Savannah , Leibowitz Shaine , Gutierrez Alejandra Rios , Passarelli Alexandra , Santo Stephanie , Shipp Nora
Published: September 2021

Throughout the COVID-19 pandemic, certain communities have been disproportionately exposed to detrimental health outcomes and socioeconomic injuries. Quantifying community needs is crucial for identifying testing and service deserts, effectively allocating resources, and informing funding and decision making. We have constructed research-driven metrics measuring the public health and economic impacts of COVID-19 on vulnerable populations. In this work we further examine and validate these indices by training supervised models to predict proxy outcomes and analyzing the feature importances to identify gaps in our original metric design. The indices analyzed in this work are unique among COVID-19 risk assessments due to their robust integration of disparate data sources. Together, they enable more effective responses to COVID-19 driven health inequities.
A condensate dynamic instability orchestrates oocyte actomyosin cortex activation
Authors: Yan Victoria Tianjing , Narayanan Arjun , Jülicher Frank , Grill Stephan W.
Published: September 2021

A key event at the onset of development is the activation of a contractile actomyosin cortex during the oocyte-to-embryo transition. We here report on the discovery that inC. elegansoocytes, actomyosin cortex activation is supported by the emergence of thousands of short-lived protein condensates rich in F-actin, N-WASP, and ARP2/3 that form an active micro-emulsion. A phase portrait analysis of the dynamics of individual cortical condensates reveals that condensates initially grow, and then switch to disassembly before dissolving completely. We find that in contrast to condensate growth via diffusion, the growth dynamics of cortical condensates are chemically driven. Remarkably, the associated chemical reactions obey mass action kinetics despite governing both composition and size. We suggest that the resultant condensate dynamic instability suppresses coarsening of the active micro-emulsion, ensures reaction kinetics that are independent of condensate size, and prevents runaway F-actin nucleation during the formation of the first cortical actin meshwork.
The origin and evolution of pollen transport in bees (Hymenoptera: Anthophila)
Authors: Portman Zachary M.
Published: September 2021

The ability to transport pollen from flowers back to the nest represents a key innovation in the evolution of bees from predatory wasp ancestors. Currently, the origin and evolution of pollen transport remains unsettled. Older hypotheses proposed that crop transport was the original mode of pollen transport, but more recent molecular phylogenies have cast doubt on that view. Instead, more recent hypotheses contend that external transport of dry pollen is ancestral in bees. Here, I propose a new hypothesis to explain the origin and subsequent evolution of pollen transport in bees. I propose that pollen transport arose from adult pollen-feeding behavior and that internal transport of pollen is ancestral in bees. This then led to the evolution of external moist transport, which first required a transition step whereby pollen is temporarily accumulated on the venter on a patch of specialized hairs. Finally, external glazed and dry transport evolved from external moist pollen transport, and the evolution of dry transport led to changes in the location of scopae from the original location on the hind tibia and basitarsus. I illustrate many of these hypothetical evolutionary steps using modern-day bee behavior as an example, with a particular focus on the beePerdita tortifoliae. Examination of the evolution of pollen transport of pollen wasps (subfamily Masarinae) reveals that they have undergone a parallel evolutionary change. Overall, I lay out a broad hypothetical framework to explain the origin and subsequent evolution of pollen transport in bees. This marks a return to the earlier hypothesis that crop transport is ancestral, and it also represents the first in-depth hypothesis to explain how external transport of moistened pollen could have evolved. The evolutionary history of bees has many implications for the biology of bees in the present day, and I lay out a number of predictions that could help confirm or refute my hypotheses.
Density-independent processes decouple component and ensemble density feedbacks
Authors: Bradshaw Corey J. A. , Herrando-Pérez Salvador
Published: September 2021

Analysis of long-term trends in abundance provide insights into population dynamics. Population growth rates are the emergent interplay of fertility, survival, and dispersal, but the density feedbacks on some vital rates (component) can be decoupled from density feedback on population growth rates (ensemble). However, the mechanisms responsible for this decoupling are poorly understood. We simulated component density feedbacks on survival in age-structured populations of long-living vertebrates and quantified how imposed nonstationarity (density-independent mortality and variation in carrying-capacity) modified the ensemble feedback signal estimated from logistic-growth models to the simulated abundance time series. The statistical detection of ensemble density feedback was largely unaffected by density-independent processes, but catastrophic and proportional mortality eroded the effect of density-dependent survival on ensemble-feedback strength more strongly than variation in carrying capacity. Thus, phenomenological models offer a robust approach to capture density feedbacks from nonstationary census data when density-independent mortality is low.
A deep dilated convolutional residual network for predicting interchain contacts of protein homodimers
Authors: Roy Raj S. , Quadir Farhan , Soltanikazemi Elham , Cheng Jianlin
Published: September 2021

Motivation

Deep learning has revolutionized protein tertiary structure prediction recently. The cutting-edge deep learning methods such as AlphaFold can predict high-accuracy tertiary structures for most individual protein chains. However, the accuracy of predicting quaternary structures of protein complexes consisting of multiple chains is still relatively low due to lack of advanced deep learning methods in the field. Because interchain residue-residue contacts can be used as distance restraints to guide quaternary structure modeling, here we develop a deep dilated convolutional residual network method (DRCon) to predict interchain residue-residue contacts in homodimers from residue-residue co-evolutionary signals derived from multiple sequence alignments of monomers, intrachain residue-residue contacts of monomers extracted from true/predicted tertiary structures or predicted by deep learning, and other sequence and structural features.

Results

Tested on three homodimer test datasets (Homo_std dataset, DeepHomo dataset, and CASP14-CAPRI dataset), the precision of DRCon for top L/5 interchain contact predictions (L: length of monomer in a homodimer) is 43.46%, 47.15%, and 24.81% respectively, which is substantially better than two existing deep learning interchain contact prediction methods. Moreover, our experiments demonstrate that using predicted tertiary structure or intrachain contacts of monomers in the unbound state as input, DRCon still performs reasonably well, even though its accuracy is lower than when true tertiary structures in the bound state are used as input. Finally, our case study shows that good interchain contact predictions can be used to build high-accuracy quaternary structure models of homodimers.

Availability

The source code of DRCon is available athttps://github.com/jianlin-cheng/DRCon.

Contact

chengji@missouri.edu
Facile synthesis of crosslinked Cu:ZnS-lignocellulose nanocomposite: a potent antifungal and antisporulant system against the tea pathogen Exobasidium vexans
Authors: Chaliha Chayanika , Baruah Julie , Kalita Eeshan
Published: September 2021

The objective of the present study was to synthesize Cu doped ZnS nanocore crosslinked with lignocellulose (represented as Cu:ZnS-lignocellulose nanocomposite) for antifungal action against the devastating tea blister blight pathogen Exobasidium vexans. The characteristic features of the nanocomposite were analyzed via different physicochemical techniques like FTIR, XRD, XPS, SEM, SEM-EDX, Elemental mapping, PCS, and UV-PL studies. The FTIR and XPS investigations revealed the crosslinking between lignocellulose and the Cu:ZnS. The presence of lignocellulose was seen to attribute a potent antifungal efficacy, also enhancing the stability of the resulting nanocomposite in aqueous suspensions. The antifungal efficacy confirmed through disk diffusion and broth dilution assays have a maximum zone of inhibition of 1.75 cm2 and a MIC50 of 0.05 mg/ml against E. vexans. Additionally, the antisporulant activity was evident as the basidiospores failed to germinate in presence of the Cu:ZnS-lignocellulose nanocomposites. This shows potential for stemming the rapid infectivity of E. vexans by achieving disease inhibition at the early stage. Finally, the comparison with two commonly used commercial fungicides (copper oxychloride and fluconazole) demonstrated >10-fold higher antifungal activity for Cu:ZnS-lignocellulose nanocomposites.
High Resolution Ancestry Deconvolution for Next Generation Genomic Data
Authors: Hilmarsson Helgi , Kumar Arvind S. , Rastogi Richa , Bustamante Carlos D. , Montserrat Daniel Mas , Ioannidis Alexander G.
Published: September 2021

As genome-wide association studies and genetic risk prediction models are extended to globally diverse and admixed cohorts, ancestry deconvolution has become an increasingly important tool. Also known as local ancestry inference (LAI), this technique identifies the ancestry of each region of an individual’s genome, thus permitting downstream analyses to account for genetic effects that vary between ancestries. Since existing LAI methods were developed before the rise of massive, whole genome biobanks, they are computationally burdened by these large next generation datasets. Current LAI algorithms also fail to harness the potential of whole genome sequences, falling well short of the accuracy that such high variant densities can enable. Here we introduce Gnomix, a set of algorithms that address each of these points, achieving higher accuracy and swifter computational performance than any existing LAI method, while also enabling portable models that are particularly useful when training data are not shareable due to privacy or other restrictions. We demonstrate Gnomix (and its swift phase correction counterpart Gnofix) on worldwide whole-genome data from both humans and canids and utilize its high resolution accuracy to identify the location of ancient New World haplotypes in the Xoloitzcuintle, dating back over 100 generations. Code is available at https://github.com/AI-sandbox/gnomix.
A bipartite chromatophore targeting peptide and N-terminal processing of proteins in the Paulinella chromatophore
Authors: Oberleitner Linda , Perrar Andreas , Macorano Luis , Huesgen Pitter F. , Nowack Eva C. M.
Published: September 2021

The cercozoan amoeba Paulinella chromatophora contains photosynthetic organelles - termed chromatophores - that evolved from a cyanobacterium ∼100 million years ago, independently from plastids in plants and algae. Despite its more recent origin, at least one third of the chromatophore proteome consists of nucleus-encoded proteins that are imported by an unknown mechanism across the chromatophore double envelope membranes. Chromatophore-targeted proteins fall into two classes. Proteins exceeding 250 amino acids carry a conserved N-terminal sequence extension, termed the ‘chromatophore transit peptide’ (crTP), that is presumably involved in guiding these proteins into the chromatophore. Short imported proteins do not carry discernable targeting signals. To explore whether the import of protein is accompanied by their N-terminal processing, here we used a mass spectrometry-based approach to determine protein N-termini in Paulinella chromatophora and identified N-termini of 208 chromatophore-localized proteins. Our study revealed extensive N-terminal modifications by acetylation and proteolytic processing in both, the nucleus and chromatophore-encoded fraction of the chromatophore proteome. Mature N-termini of 37 crTP-carrying proteins were identified, of which 30 were cleaved in a common processing region. Our results imply that the crTP mediates trafficking through the Golgi, is bipartite and surprisingly only the N-terminal third (‘part 1’) becomes cleaved upon import, whereas the rest (‘part 2’) remains at the mature proteins. In contrast, short imported proteins remain largely unprocessed. Finally, this work sheds light on N-terminal processing of proteins encoded in an evolutionary-early-stage photosynthetic organelle and suggests host-derived post-translationally acting factors involved in dynamic regulation of the chromatophore-encoded chromatophore proteome.

One sentence summary

Proteins targeted to the evolutionary-early-stage photosynthetic organelle of Paulinella carry a bipartite N-terminal targeting sequence that is only partially removed upon protein import.
Field clinical performance of SARS-CoV-2 point-of-care diagnostic tests: a living systematic review of trials up to 17th of August, 2021
Authors: Hawthorne Gabriel , Harvey Adam
Published: September 2021

Point-of-care assays offer a decentralized and fast solution to the diagnosis of SARS-CoV-2, providing benefits for patients, healthcare workers and healthcare facilities. This technology has the potential to prevent outbreaks, enable fast adoption of potentially life-saving measures and improve hospital workflow. While reviews regarding the laboratory performance of those assays exist, a review focused on the real-life clinical performance and true point-of-care feasibility of those platforms is missing. Therefore, the objective of this study is to help clinicians, healthcare providers and organizations to understand the real-life performance of point-of-care assays, aiding in their implementation in decentralised, true point-of-care facilities, or inside hospitals. 1246 studies were screened in 3 databases and 87 studies were included, evaluating 27 antigen tests and 11 nucleic-acid amplification platforms deemed feasible for true point-of-care placement. We excluded studies that used processed samples, pre-selected populations, archived samples and laboratory-only evaluations and strongly favored prospective trial designs. We also investigated package inserts, instructions for use, comments on published studies and manufacturer’s websites in order to assess feasibility of point-of-care placement and additional information of relevance to the end-user. Apart from performance in the form of sensitivity and specificity, we present information on time to results, hands-on time, kit storage, machine operating conditions and regulatory status. To the best of our knowledge, this is the first review to systematically compare point-of-care test performance in real-life clinical practice. We found the performance of tests in clinical practice to be markedly different from the manufacturers reported performance and laboratory- only evaluations in the majority of scenarios. Our findings may help in the decision-making process related to SARS-CoV-2 test in real-life clinical settings.

Rationale for the review

A review focused on the real-life clinical performance and point-of-care feasibility of SARS-CoV-2 diagnostic platforms is missing, impairing the ability of individuals, healthcare providers and test providers to make informed decisions.

Objective(s) or question(s) the review addresses

The objective of this study is to help clinicians, healthcare providers and organizations to understand the real-life performance of point-of-care assays, aiding in their implementation in decentralised, true point-of-care facilities or in complex healthcare environments.
Long Term Accuracy of SARS-CoV-2 Interferon-γ Release Assay and its Application in Household Investigation
Authors: Murugesan Kanagavel , Jagannathan Prasanna , Altamirano Jonathan , Maldonado Yvonne A , Bonilla Hector F. , Jacobson Karen B. , Parsonnet Julie , Andrews Jason R. , Shi Run-Zhang , Boyd Scott , Pinsky Benjamin A. , Singh Upinder , Banaei Niaz
Published: September 2021

Background

An immunodiagnostic assay that sensitively detects a cell-mediated immune response to SARS-CoV-2 is needed for epidemiological investigation and for clinical assessment of T cell-mediated immune response to vaccines, particularly in the context of emerging variants that might escape antibody responses.

Methods

The performance of a whole blood interferon-gamma (IFN-γ) release assay (IGRA) for the detection of SARS-CoV-2 antigen-specific CD4 and CD8 T cells was evaluated in COVID-19 convalescents tested serially up to 10 months post-infection and in healthy blood donors. SARS-CoV-2 IGRA was applied in contacts of households with index cases. Freshly collected blood in the lithium heparin tube was left unstimulated, stimulated with a SARS-CoV-2 peptide pool, and stimulated with mitogen.

Results

The overall sensitivity and specificity of IGRA were 84.5% (153/181; 95% confidence interval [CI] 79.0-89.0) and 86.6% (123/142; 95% CI;80.0-91.2), respectively. The sensitivity declined from 100% (16/16; 95% CI 80.6-100) at 0.5-month post-infection to 79.5% (31/39; 95% CI 64.4-89.2) at 10 months post-infection (P<0.01). The IFN-γ response remained relatively robust at 10 months post-infection (3.8 vs. 1.3 IU/mL, respectively). In 14 households, IGRA showed a positivity rate of 100% (12/12) and 65.2% (15/23), and IgG of 50.0% (6/12) and 43.5% (10/23) in index cases and contacts, respectively, exhibiting a difference of +50% (95% CI +25.4-+74.6) and +21.7% (95% CI, +9.23-+42.3), respectively. Either IGRA or IgG was positive in 100% (12/12) of index cases and 73.9% (17/23) of contacts.

Conclusions

The SARS-CoV-2 IGRA is a useful clinical diagnostic tool for assessing cell-mediated immune response to SARS-CoV-2.

Key points

SARS-CoV-2 immunodiagnostics are needed to identify infected individuals in order to understand the transmission dynamics of emerging variants and to assess vaccine response. Interferon-gamma release assay maintains sensitivity 10 months post-infection in convalescents and detects more household contacts than IgG.
Health-care workers in gastrointestinal endoscopy are at higher risk for SARS-CoV-2 infection compared to other aerosol-generating disciplines
Authors: Römmele Christoph , Ebigbo Alanna , Kahn Maria , Zellmer Stephan , Muzalyova Anna , Hammel Gertrud , Bartenschlager Christina , Beyer Albert , Rosendahl Jonas , Schlittenbauer Tilo , Zenk Johannes , Al-Nawas Bilal , Frankenberger Roland , Hoffmann Jürgen , Arens Christoph , Lammert Frank , Traidl-Hoffmann Claudia , Messmann Helmut
Published: September 2021

Objective

Healthcare workers (HCW) are at high risk of SARS-CoV-2 infection due to exposure to potentially infectious material, especially during aerosol-generating procedures (AGP). We aimed to investigate the prevalence of infection among HCW in medical disciplines with AGP.

Design

A nationwide questionnaire-based study in in- and outpatient settings was conducted between 12/16/2020 and 01/24/2021. Data on SARS-CoV-2 infections among HCW and potential risk factors were investigated.

Results

2,070 healthcare facilities with 25,113 employees were included in the study. Despite a higher rate of pre-interventional testing, clinics treated three times more confirmed SARS-CoV-2 cases than private practices (28.8% vs. 88.4%, p<0.001). Overall infection rate among HCW accounted for 4.7%. Multivariate analysis revealed that ZIP-regions having comparably higher incidences were significantly associated with increased risk of infection. Furthermore, clinical setting and the GIE specialty have more than double the risk of infection (OR 2.63; 95% CI 2.501-2.817, p<0.01 and OR 2.35; 95% CI 2.245-2.498, p<0.01). The number of procedures performed per day was also significantly associated with an increased risk of infection (OR 1.01; 95% CI 1.007-1.014), p<0.01). No treatment of confirmed SARS-CoV-2 cases was tending to lower the risk of infection (OR 0.72; 95% CI 0.507-1.025, p=0.068).

Conclusion

HCW in GIE seem to be at higher risk of infection than those in other AGP, especially in the clinical setting. Regions having comparably higher incidences as well as the number of procedures performed per day were also significantly associated with increased risk of infection.

Significance of this study

What is already known on this subject?

Health care workers, especially those exposed to aerosol generating procedures, are assumed to have an increased risk of SARS-CoV-2 infection. However, data confirming this are lacking, especially for the outpatient care setting.

What are the new findings?

Health care workers in gastrointestinal endoscopy have a higher risk of SARS-CoV-2-infection than in other AGPs. This risk is particularly higher

-

in clinical settings compared to private practices

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in regions having comparably higher incidences

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the more procedures are performed per day

How might it impact on clinical practice in the foreseeable future?

Our study suggests making additional efforts to protect HCW in the gastrointestinal work field.
Human Milk Antibodies Elicited by BNT162b2 Vaccination have reduced activity against SARS-CoV-2 Variants of Concern
Authors: Low Jia Ming , Gu Yue , Ng Melissa Shu Feng , Wang Liang Wei , Amin Zubair , Zhong Youjia , MacAry Paul A
Published: September 2021

We detected the presence of SARS-CoV-2 specific IgA against all major VOCs in milk out to 6 weeks after D2 of BNT162b2. These likely confer some protection to the breastfed infants, who are ineligible for vaccination and are at risk of severe COVID-19.

However, we detected significantly reduced milk IgA binding to VOCs, including the globally dominant Delta variant, suggesting reduced protection for breastfeeding infants. Additionally, these antibodies were significantly reduced by as early as 4-6 weeks after D2.
Health-Related Quality of Life and psychological distress of adolescents during the COVID-19 pandemic in Geneva
Authors: Dumont Roxane , Richard Viviane , Baysson Hélène , Lorthe Elsa , Piumatti Giovanni , Schrempft Stephanie , Wisniak Ania , Barbe Rémy P. , Posfay-Barbe Klara M. , Guessous Idris , Stringhini Silvia
Published: September 2021

Abstract

Purpose

Our objective was to assess adolescent’s Health-Related Quality of Life (HRQoL) and psychological distress, from their own and their parents’ perspective, and to examine associated risk factors during the COVID-19 pandemic in Geneva, Switzerland.

Methods

A random sample of adolescents, aged 14-17 years, and their families was invited to a serosurvey in November and December 2020. Adolescents’ HRQoL was evaluated using the validated adolescent-reported KIDSCREEN-10 and parent-reported KINDL®scales. Psychological distress was assessed with self-reported sadness and loneliness, and using the KINDL®emotional well-being scale. Risk factors for adolescents’ low HRQoL and psychological distress were identified using generalized estimating equations and both adolescents’ and their parents’ perceptions were compared.

Results

Among 240 adolescents, 11% had a low HRQoL, 35% reported sadness and 23% reported loneliness. Based on parents’ perception, 12% of the adolescents had a low HRQoL and 16% a low emotional well-being. Being a girl (aOR=3.29; 95%CI: 1.64-6.57), increased time on social media (aOR=2.05; 95%CI: 1.08-3.88), parents’average to poormood (aOR=2.81; 95%CI: 1.21-6.56) andaverage to poorhousehold financial situation (aOR=2.30; 95%CI: 1.00-5.29) were associated with an increased risk of sadness. Mismatches between adolescents’ and their parents’ perception of HRQoL were more likely for girls (aOR=2.88; 95%CI: 1.54-5.41) and in households with lower family well-being (aOR=0.91; 95%CI: 0.86-0.96).

Conclusion

A meaningful proportion of adolescents experienced low well-being during the second wave of COVID-19. Adolescents living in underprivileged or distressed families seemed particularly affected. Monitoring is necessary to evaluate the long-term effects of the pandemic on adolescents.

Implications and Contribution

This study describes the psychological well-being of a population-based sample of adolescents in Geneva, Switzerland amid the COVID-19 pandemic, and identifies adolescents at risk of distress. This study provides further insight by comparing adolescents’ well-being as reported by themselves and their parents.
HUMORAL AND CELLULAR IMMUNOGENICITY and SAFETY UP TO 4 MONTHS AFTER VACCINATION WITH BNT162B2 mRNA COVID-19 VACCINE IN HEART AND LUNG TRANSPLANTED YOUNG ADULTS
Authors: Cotugno Nicola , Pighi Chiara , Morrocchi Elena , Ruggiero Alessandra , Amodio Donato , Medri Chiara , Colagrossi Luna , Russo Cristina , Cesare Silvia Di , Santilli Veronica , Manno Emma Concetta , Zangari Paola , Giancotta Carmela , Bernardi Stefania , Nicolosi Luciana , Degli Atti Marta Ciofi , Raponi Massimiliano , Zaffina Salvatore , Alfieri Sara , Kirk Richard , Perno Carlo Federico , Rossi Paolo ,   CONVERS study Team, Amodeo Antonino , Palma Paolo
Published: September 2021

Background

Immunizations among vulnerable population, including solid organ transplant recipients (SOT), present suboptimal responses at vaccination and over time. We investigated safety and immunogenicity of the BNT162B2 mRNA COVID-19 vaccine in 34 SOT young adults as compared to 36 healthy controls (HC).

Methods

immunogenicity was measured through the analysis of anti SARS-CoV2 IgG Antibodies and antigen specific CD4 T cells (CD40L+), detected by flow cytometry before vaccination, 21 days after priming (T21), 7 days after booster dose (T28) and 2-4 months after priming (T120). Baseline T and B cell immune phenotype was deeply investigated. The safety profile was investigated by close monitoring and self-reported diary.

Results

Anti-S and anti-Trimeric Ab responses were significantly lower in SOT vs HC at T21 (p<0.0001) and at T28 (p<0.0001). Ten out of 34 SOT (29%) at T28 and 3 out of 33 (9%) at T120 had undetectable SARS-CoV-2 IgG. The analysis of SARS-CoV-2 specific CD4 T cells showed lower CD40L expression after in vitro stimulation in SOT compared to HC. Lower frequencies of memory B cells were found in patients not responding to vaccination. Lack of seroconversion was higher in patients treated with mycophenolate (p=0.0005). The vaccination was safe and well tolerated. Only short-term adverse events, were reported and no hospitalization or graft rejection were observed after vaccinations.

Conclusions

These data show that SOT have a suboptimal immune response following mRNA vaccinations as compared to HC. Alternative strategies should be investigated to improve the immunization against SARS-CoV-2 in these patients.
Childhood Asthma and COVID-19: A Nested Case-Control Study
Authors: Gaietto Kristina , Freeman Megan Culler , DiCicco Leigh Anne , Rauenswinter Sherry , Squire Joseph R , Aldewereld Zachary , Iagnemma Jennifer , Campfield Brian T , Wolfson David , Kazmerski Traci M , Forno Erick
Published: September 2021

Background

Most pediatric studies of asthma and COVID-19 to date have been ecological, which offer limited insight. We evaluated the association between asthma and COVID-19 at an individual level.

Methods

Using data from prospective clinical registries, we conducted a nested case-control study comparing three groups: children with COVID-19 and underlying asthma (“A+C” cases); children with COVID-19 without underlying disease (“C+” controls); and children with asthma without COVID-19 (“A+” controls).

Results

The cohort included 142 A+C cases, 1110 C+ controls, and 140 A+ controls. A+C cases were more likely than C+ controls to present with dyspnea and wheezing, to receive pharmacologic treatment including systemic steroids (all p<0.01), and to be hospitalized (4.9% vs 1.7%, p=0.01). In the adjusted analysis, A+C cases were nearly 4 times more likely to be hospitalized than C+ controls (adjusted OR=3.95 [95%CI=1.4-10.9]); however, length of stay and respiratory support level did not differ between groups. Among A+C cases, 8.5% presented with an asthma exacerbation and another 6.3% developed acute exacerbation symptoms shortly after testing positive for SARS-CoV-2. Compared to historic A+ controls, A+C cases had less severe asthma, were less likely to be on controller medications, and had better asthma symptom control (all p<0.01).

Conclusions

In our cohort, asthma was a risk factor for hospitalization in children with COVID-19, but not for worse COVID-19 outcomes. SARS-CoV-2 does not seem to be a strong trigger for pediatric asthma exacerbations. Asthma severity was not associated with higher risk of COVID-19.

Key messages

In this pediatric cohort, asthma was a risk factor for hospitalization in children with COVID-19, but not for worse COVID-19 outcomes. Baseline asthma severity was not associated with higher risk of COVID-19, and SARS-CoV-2 did not seem to be a strong trigger for pediatric asthma exacerbations.
The impact of health literacy-sensitive design and heart age in a cardiovascular disease prevention decision aid: randomised controlled trial and end user testing
Authors: Bonner Carissa , Batcup Carys , Ayre Julie , Cvejic Erin , Trevena Lyndal , McCaffery Kirsten , Doust Jenny
Published: September 2021

Introduction

Shared decision making is as an essential principle for cardiovascular disease (CVD) prevention, where asymptomatic people are considering lifelong medication and lifestyle changes. This project aimed to develop and evaluate the first literacy-sensitive CVD prevention decision aid (DA) developed for people with low health literacy, and investigate the impact of literacy-sensitive design and heart age.

Methods

We developed the standard DA based on international standards. The literacy-sensitive version included simple language, supporting images, white space and a lifestyle action plan. A randomised trial included 859 people aged 45-74 using a 3 (DA: standard, literacy-sensitive, control) x 2 (heart age: heart age + percentage risk, percentage risk only) factorial design, with outcomes including prevention intentions/behaviours, gist/verbatim knowledge of risk, credibility, emotional response and decisional conflict. We iteratively improved the literacy-sensitive version based on end user testing interviews with 20 people with varying health literacy levels.

Results

Immediately post-intervention (n=859), there were no differences between the DA groups on any outcome. The heart age group was less likely to have a positive emotional response, perceived the message as less credible, and had higher gist/verbatim knowledge of heart age risk but not percentage risk. After 4 weeks (n=596), the DA groups had better gist knowledge of percentage risk than control. The literacy-sensitive decision aid group had higher fruit consumption, and the standard decision aid group had better verbatim knowledge of percentage risk. Verbatim knowledge was higher for heart age than percentage risk amongst those who received both.

Discussion

The literacy-sensitive DA resulted in increased knowledge and lifestyle change for participants with varying health literacy levels and CVD risk results. Adding heart age did not increase lifestyle change intentions or behaviour but did affect psychological outcomes, consistent with previous findings.

MeSH Terms

Health Literacy, Cardiovascular Diseases, Decision Making (Shared), Life Style, Decision Support Techniques
Proton export drives the Warburg Effect
Authors: Russell Shonagh , Xu Liping , Kam Yoonseok , Abrahams Dominique , Verduzco Daniel , Johnson Joseph , Epstein Tamir , Ruiz Epifanio , Lloyd Mark C. , Wojtkowiak Jonathan , Lopez Alex S. , Bui Marilyn M. , Gillies Robert J. , Swietach Pawel , Ordway Bryce
Published: September 2021

Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the “Warburg Effect”. It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, including the terminal step of exporting H+ equivalents from the cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which can enhance all glycolytic enzyme activities, even in the absence of oncogene-related expression changes. Based on this observation, we hypothesized that increased uptake and fermentative metabolism of glucose could be driven by the expulsion of H+ equivalents from the cell. To test this hypothesis, we stably transfected lowly-glycolytic MCF-7, U2-OS, and glycolytic HEK293 cells to express proton exporting systems: either PMA1 (yeast H+-ATPase) or CAIX (carbonic anhydrase 9). The expression of either exporter in vitro enhanced aerobic glycolysis as measured by glucose consumption, lactate production, and extracellular acidification rate. This resulted in an increased intracellular pH, and metabolomic analyses indicated that this was associated with an increased flux of all glycolytic enzymes upstream of pyruvate kinase. These cells also demonstrated increased migratory and invasive phenotypes in vitro, and these were recapitulated in vivo by more aggressive behavior, whereby the acid-producing cells formed higher grade tumors with higher rates of metastases. Neutralizing tumor acidity with oral buffers reduced the metastatic burden. Therefore, cancer cells with increased H+ export increase intracellular alkalization, even without oncogenic driver mutations, and this is sufficient to alter cancer metabolism towards a Warburg phenotype.
Calculating the force-dependent unbinding rate of biological macromolecular bonds from the force-ramp optical trapping assays
Authors: Paul Apurba , Alper Joshua
Published: September 2021

The non-covalent biological bonds that constitute protein-protein or protein-ligand interactions play crucial roles in many cellular functions, including mitosis, motility, and cell-cell adhesion. The effect of external force (F) on the unbinding rate (koff(F)) of macromolecular interactions is a crucial parameter to understanding the mechanisms behind these functions. Optical tweezer-based single-molecule force spectroscopy is frequently used to obtain quantitative force-dependent dissociation data on slip, catch, and ideal bonds. However, analyses of this data using dissociation time or dissociation force histograms often quantitatively compare bonds without fully characterizing their underlying biophysical properties. Additionally, the results of histogram-based analyses can depend on the rate at which force was applied during the experiment and the experiment’s sensitivity. Here, we present an analytically derived cumulative distribution function-like approach to analyzing force-dependent dissociation force spectroscopy data. We demonstrate the benefits and limitations of the technique using stochastic simulations of various bond types. We show that it can be used to obtain the detachment rate and force sensitivity of biological macromolecular bonds from force spectroscopy experiments by explicitly accounting for loading rate and noisy data. We also discuss the implications of our results on using optical tweezers to collect force-dependent dissociation data.
Identification of topoisomerase as a precision-medicine target in chromatin reader SP140-driven Crohn’s disease
Authors: Amatullah Hajera , Digumarthi Sreehaas , Fraschilla Isabella , Adiliaghdam Fatemeh , Bonilla Gracia , Wong Lai Ping , Sadreyev Ruslan I. , Jeffrey Kate L.
Published: September 2021

How mis-regulated chromatin directly impacts human immunological disease is poorly understood. Speckled Protein 140 (SP140) is an immune-restricted PHD and bromodomain-containing chromatin ‘reader’ whose loss-of-function associates with Crohn’s disease (CD), multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL). However, mechanisms underlying SP140-driven pathogenicity and therapeutic approaches that rescue SP140 remain unexplored. Using a global proteomic strategy, we identified SP140 as a repressor of topoisomerases (TOP) that maintains heterochromatin and immune cell fate. In humans and mice, SP140 loss resulted in unleashed TOP activity, genome instability, severely compromised lineage-defining and microbe-inducible innate transcriptional programs and defective bacterial killing. Pharmacological inhibition of TOP1 or TOP2 rescued these defects. Furthermore, exacerbated colitis was restored with TOP1 or TOP2 inhibitors in Sp140−/− mice, but not wild-type mice, in vivo. Collectively, we identify SP140 as a repressor of topoisomerases and reveal repurposing of TOP inhibition as a precision strategy for reversing SP140-driven immune disease.